T

 OpioidsintheSpinalCordandModulationofAscend- Tabes Dorsalis ing Pathways (N. gracilis)

Definition A late complication of neurosyphilis. It results in gait impairment, joint deformity, pain, lack of coordination, Tactile Allodynia Test sensory loss, as well as autonomic dysfunction and oc- ular symptoms. Pain is felt mostly in the legs and is de- Definition scribed as lightning and lancinating. Abdominal colicky The plantar aspects of intact and neuropathic legs of rats pain is also reported.  are probed with Von Frey hairs of different calibers or Central Nervous System Stimulation for Pain strengths. The number of paw withdrawals per 10 trials is counted. In general, a number of 5/10 withdrawals is observed with hairs of strength > 20 g in rats with intact Tachykinin legs, and in rats with mononeuropathy, a hair of 2 g can produce a score of > 5/10 withdrawals. Definition  Thalamotomy, Pain Behavior in Animals Tachykinins are a family of structurally-related pep- tides, widely scattered in vertebrate and invertebrate tissues. Mammalian tachykinins are substance P (SP), Tactile Stimuli neurokinin A (NKA), and neurokinin B (NKB). All mammalian tachykinins share a common C-terminal amino acid sequence, i.e. Phe-x-Gly-Leu- MetNH, Definition which is the minimal structural motif for the activation Stimuli of light touch applied to the skin. of tachykinin receptors (NK1, NK2 and NK3). Phar-  Causalgia, Assessment macologically, they all cause hypotension in mammals,  Dysesthesia, Assessment contraction of gut and bladder smooth muscle, and secretion of saliva.  Neuropeptide Release in the Skin  NGF, Regulation during Inflammation Tail Immersion  Visceral Nociception and Pain Definition Submersion of the tail in hot water may be used as the Tachyphylaxis nociceptive stimulus in the Tail-Flick Test.  Tail-Flick Test  Nociceptor, Fatigue

Tactile Allodynia Tail Skin Temperature Recording

Definition Definition Tactile allodynia refers to touch-evoked pain, i.e. pain Thermocouples, thermistors or infrared sensors may be due to a mechanical stimulus that does notnormally pro- used. voke pain.  Tail-Flick Test 2392 Tail-Flick Latency

performed in lightly anaesthetized rats or mice, as well Tail-Flick Latency as in animals that are awake. Several tail–flick apparatuses are commercially avail- Definition able, and many laboratories have made their own appa- Tail-Flicklatencyisthetimefromthestartofthenoxious ratus. The main requirements are stable functioning and stimulus until the animal flicks its tail. proper focus of the light beam on the tail. The tail–flick  Tail-Flick Test latency may be recorded by means of a photocell, which isactivatedwhentheanimalflicksthetail.Whenaphoto- cell is used, one should be aware that the reflex response may involve retracting the tail, without immediately re- Tail-Flick Latency Correction moving the tail from the light beam. Thus the rats’ be- haviour should always be observed. Definition The tail–flick test may be a good and useful test of noci- The tail-flick latency may be corrected for influences of ception, but only if it is carefully performed and possible tail skin temperature using a regression analysis or anal- sourcesoferroraretakenintoaccount.Onerequirement, ysis of covariance. Linearity of the data can be assumed particularly in rats, is that the animals are well handled. only for a limited range of skin temperatures. In some Thismay requiredaily handling forupto aweek, includ- experiments preheating of the tail to a certain tempera- ing adaptation to the test apparatus. Some researchers ture may be used. confine the animals in a plastic tube during testing. If  Tail-Flick Test this is used, it is necessary that the animals are so well handled that they freely walk in and out of the tube. We find it better and faster not to use a tube, but to hold the well-adapted animal by hand. Tail Flick Test A particular problem with tests that use thermal stimu- lation is the possible confounding influence of the skin KJELL HOLE,ARNE TJØLSEN temperature. In electrophysiologicalstudies in animals, University of Bergen, Bergen, Norway it has been reported that changes in the temperature or [email protected], [email protected] blood flow of the skin (Duggan et al. 1978) alter the re- Definition sponse to cutaneous heat stimulation. More recently, it has been found that the tail skin temperature affects the The tail–flick test is a test of nociception used in rats and tail–flick latency as well. This has been described using mice. The noxious stimulus is usually  radiant heat on radiant heat stimulation (Ren and Han 1979; Berge et the tail or  tail immersion in hotwater, andtheresponse al. 1988; Roane et al. 1998; Sawamura et al. 2002) as is a flick of the tail. well as with hot water immersion of the tail (Milne and Gamble 1989). For an extensive review see Le Bars et Characteristics al. (2001). However, in many laboratories the tail–flick The tail–flick test is an extensively used test of nocicep- testisstillperformed withouttaking the tailskin temper- tion in rats and mice, and is the nociceptive test most ature into account. This is probably a main confounding frequently used in animals (Le Bars et al. 2001), first factor, and therefore needs special consideration in the described in 1941 (D’Amour and Smith 1941). In the following. standard method, radiant heat is focused on the tail, and We have investigated the relationship between skin sur- the time it takes until the animal flicks the tail away from face temperature and tail–flick latency in rats in a setup the beam is measured. This  tail–flick latency is a mea- with a radiant heat apparatus, stimulating the distal part sure of the nociceptive sensitivity of the animal, and is of the tail (10–15 mm from the tip), with a stimulated prolonged by opioid analgesics, for instance. A spinal area of 15–20 mm2 (Fig. 1). Using control latencies of transection above the lumbar level does not block the approximately 4s, we regularly find a clear and repro- tail–flick response. Thus, in this test, a spinal nocicep- ducible relationship between tail skin temperature and tivereflexismeasured,andpainisnotmeasureddirectly. tail–flick latency, with a slope of the regression equa- Still,thisisconsideredaveryusefultestof“phasicpain”, tion of –0.3 – 0.4s/˚C (Tjølsen et al. 1989). With similar bothinbasicpainresearchandinpharmacologicalinves- methodology, the same relationship has been found in tigationsofanalgesicdrugs.Therelevanceofthetestasa mice, with a very similar slope (Eide et al. 1988). measure of pain hasbeen discussed (LeBarsetal. 2001). The tail is the most important thermoregulatory organ of The test stimulus is noxious heat. In addition to the test the rat. The heat loss is regulated by an on–off regulation with radiant heat (e.g. focused light from a light bulb), ofbloodflowinthetail,whichleadstorapidvariationsin the stimulus may be applied by e.g. direct contact with skin temperature (Milne and Gamble 1989, Tjølsen and a heated surface, such as a Peltier element, or by sub- Hole 1992). The amount and duration of vasodilation is mersion of part of the tail in hot water. The test may be partly determined by the relationship between the am- Tail Flick Test 2393

Tail Flick Test, Figure 2 The relationship between tail–flick latency and tail skin temperature. Data were obtained from eight measurements in each of 12 rats. Tail skin temperature was controlled by means of a heating blanket. Adapted from Sawamura et al. (2002), with permission.

for each time point (Tjølsen et al. 1989). In fact, if re- peated measures on the same animals are pooled in a re- gression analysis, an error in the calculated slope may be introduced. A possible cause of error is the effect of re- peatedtestingonnociceptionitself,whetherduetostress or to local effects in the skin if the same site is stimu- lated repeatedly. The time required for heating the tissue to a critical response temperature will depend on the ini- tialskintemperature,whichisdeterminedbylocalblood Tail Flick Test, Figure 1 Simple test equipment for concomitant record- flow within the limits given by deep body and ambient ing of tail skin temperatures and tail–flick latencies. A standard tail–flick temperatures. Measuring subcutaneous tissue tempera- apparatus can easily be modified to enable recording of tail skin temper- tures during a radiant heat stimulus, we found that the T atures. The temperature is measured by means of a small thermocouple rate of increase in tissue temperature wasindependentof mounted on a plastic arm, 65 mm long, which rests on the tail with a force corresponding to approximately 1g. For a thorough description see initial skin temperature, and the time required to reach a Tjølsen et al. (1989). hypothetical threshold temperature was strongly depen- dent on the initial temperature (Hole and Tjølsen 1993). Asaconsequence,thetail–flicklatencyisnegativelycor- bient temperature and the acclimatization temperature. related to the ambient temperature (Berge et al. 1988) In rats at rest, the ambient temperature where vasodila- andtoskintemperaturewhentheheatingintensityiskept tion occurs is lower after acclimatization to cold, than constant. after acclimatization to a warmer environment. When The temperature of the tail skin of rats during an ex- animals are lightly stressed and activated due to exper- periment may rise as much as 8˚C in untreated animals imental procedures, a considerable increase in tail skin (Tjølsen and Hole 1992). It is reasonable to consider temperature is regularly observed (Tjølsen et al. 1989). this is the maximal possible difference in skin temper- Rats restrained in tubes for a short time may show a con- ature due to changes in vasodilation. With a change siderable increase in the temperature of the tail (Tjølsen in tail–flick latency of 0.3–0.4 s/˚C, it would imply and Hole 1992), probably due to vasodilation. a potential difference in tail–flick latency of up to The relationship between skin temperatureand response approximately 3s. In a group of rats, not all animals latency (Fig. 2) would be expected to vary with different would show this degree of vasodilation, and hence the experimentalconditions.Themostreliablevaluesforthe mean difference in latency would be somewhat smaller. slope are obtained in experiments where data from re- However, this shows that increased vasoconstriction peated measures are not pooled, but analysed separately or inhibition of vasodilation may cause differences in 2394 Tail Flick Test tail–flick latency that easily could be misinterpreted as predictableconfoundingfactor.Asdiscussedabove,this analgesia. has, in several instances, lead to erroneous conclusions. The potential for treatment–induced vasodilation to cause reduction of the tail–flick latencies is approx- Possible Remedies imately the same size. Under circumstances when The temperature of the tail skin should always be con- control animals are relatively vasoconstricted, vasodi- sidered a possible confounding factor when performing lation may lead to an increase in tail skin temperature the tail–flick test. A minimal requirement should be that from about ambient temperature to above 30˚C. The ef- the tail skin temperature is measured before testing, e.g. fect of vasodilation is particularly important, as smaller by means of thermocouples (Fig. 1), thermistors or in- changes in the tail–flick latency are required to interpret frared sensors, and the possible influence of the temper- the results as hyperalgesia than as analgesia. Even a ature evaluated. modest increase in the mean tail skin temperature of It is obviously necessary to take the effects of skin about 3.5˚C, due to lesioning of descending serotoner- temperature into account when investigating factors, gic systems, leads to a reduction of the tail–flick latency or using drugs that may influence autonomic activity from 4–4.5s to about 3s (Hole and Tjølsen 1993). If and thermo – or cardiovascular regulation. Recording the change in skin temperature were not taken into the tail skin temperature and correcting the tail–flick consideration, a reduction of the tail–flick latency of latency data for changes in the temperature may reduce this size would have been considered an indication of a the problem. In some cases, a regression analysis or an hyperalgesic state. analysis of covariance may be performed for this pur- Many experimental treatments affect blood flow and pose. Methods for tail–flick testing with measurement thereby the tail skin temperature. This may by itself of skin temperature and for correction of tail–flick data influence the tail–flick latency, and lead to erroneous (see  tail-flick latency correction)have been described conclusions with regard to nociception. An increase in (Tjølsen et al. 1989; Roane et al. 1998; Sawamura et tail skin temperature may shorten tail–flick latencies al. 2002). However, there are some limitations when and may be interpreted as hyperalgesia (Urban and using this type of statistical analysis on tail–flick data. Smith 1994; Roane et al. 1998; Sawamura et al. 2002). In these statistical methods, linearity of the relationship Even a reduction in tail skin temperature compared to is supposed. It seems to be a reasonable approximation untreated animals may occur, and may be interpreted as to suppose linearity over a normal, limited range of analgesia. Desipramine reduced tail skin temperature skin temperatures in untreated animals, e.g. 20–30oC. and increased tail–flick latencies at an ambient tem- In studies where drug administration causes a large in- perature of 24–25˚C, while no significant change was creaseintail–flicklatencyduetochangesinnociception, observed at 21–22˚C (Hole and Tjølsen 1993). This the assumption of linearity may not be correct. Above difference in temperature is well within the variation all, these methods for statistical evaluation cannot ad- in ambient temperature between laboratories, and even equately handle cut-off values for tail–flick latencies. within the range of ambienttemperaturesthatmay occur This should be considered in each experiment, and even in a laboratory with insufficient control of room tem- when limitations as above are applicable, the tempera- perature. In the experiments at 24–25˚C, desipramine ture of the skin of the tail should be measured and the inhibited vasodilation so that the skin temperatures possible influence on the results should be evaluated. in the drug–treated group were close to the ambient As a number of factors may possibly influence the rela- temperature, while control animals showed higher skin tionship between skin temperatureandresponse latency, temperatures and hence shorter response latencies. itseemsidealtoadjustdatafromoneexperimentaccord- Stress, due to a new environment, handling or injection ing to the regression slope calculated from that experi- procedures, may influence peripheralblood flow and tail ment. However, this will not always be possible, in that a temperature. In rats, stress causes motor activation, in- regressionanalysisrequiresanadequatenumberofmea- creased heatproduction, increasedcore temperature and surements to allow calculation of a reliable regression an increased frequency anddurationofthe periodsof va- coefficient, and the spread of the independent variable sodilation and increase in skin temperature of the tail. It (skin temperature) must be sufficiently large. If these re- has been shown (Tjølsen et al. 1992) that immobiliza- quirements are not fulfilled, the results of the regression tion may cause a considerable increase in core tempera- analysiswillbeinconclusive.Withanincreasingnumber tureand tailvasodilation, whilesmalldosesof morphine of measurements in the analysis, there is an increasing (0.5–1mg/kg) completely abolish the vasodilation. probability that a reliable regression coefficient may be The importance of the skin temperature for the ordinary calculated. In many cases, it may be a problem to ob- use of the tail–flick test has been discussed (Roane et tain a reliable correction of tail–flick data based on the al. 1998). Clearly, when high doses of potent analgesics same experiment, due to a limited number of animals like opioids are used, the relative influence of the skin measured. An alternative method for correction of la- temperature may be small. However, when the temper- tencies is to establish the relationship between skin tem- ature influence is not known, this will always be an un- perature and tail–flick latency in an adequate number of Targeting 2395 animalsunder similar experimentalconditions, and sub- 12. Sawamura S, Tomioka T, Hanaoka K (2002) The Importance of sequently to correct tail–flick latencies according to the Tail Temperature Monitoring during Tail–Flick Test in Evalu- ating the Antinociceptive Action of Volatile Anesthetics. Acta calculated regression factor (Ren and Han 1979). This Anaesthesiol Scand 46:451–454 method should be used with caution, because it must 13. Tjølsen A, Hole K (1992) The Effect of Morphine on Core and be assumed that the experiment is performed under the Skin Temperature in Rats. NeuroReport 3:512–514 same conditions as when the correction factor was de- 14. Tjølsen A, Lund A, Berge O-G, Hole K (1989) An Improved Method for Tail–Flick Testing with Adjustment for Tail-Skin termined. This is of course an approximation. Temperature. J Neurosci Meth 26:259–265 Another alternative that has been used is local preheat- 15. Urban MO, Smith DJ (1994) Nuclei within the Rostral Ventro- ing of the tail to a certain temperature before measuring medial Medulla Mediating Morphine Antinociception from the the tail–flick latency. If the temperatures of the skin and Periaqueductal Gray. Brain Res 652:9–16 subcutaneous tissue in the stimulated area are constant before the start of stimulation, this may abolish the con- founding effect of varying tissue temperatures. In elec- trophysiological experiments in anaesthetized cats, pre- heatinghasbeenusedwithaheatinglampandafeedback Talairach Coordinates controlsystem,withathermocoupleontheareaofskinto be heated (Duggan et al. 1978). This procedure seemed Definition to reduce the confounding effect of differences in blood flow. For tail–flick reflex recordings, this technique may Initially developed for a specific stereotactic frame; be used in experiments in lightly anaesthetized animals based on one single brain; frequently used as a common for instance (Haws et al. 1990), or when the rat is placed coordinate system; X: left-right, Y: anterior-posterior, in a restrainer and the tail is fixed (Carstens and Dou- Z: superior-inferior; the reference point (0, 0, 0) is the glass 1995). It may probably be more difficult to use this anterior commissure (Talairach and Tournoux 1988). method in animals that are awake when little restraint of  Nociceptive Processing in the Secondary Somatosen- the animal is required to minimize stress. sory Cortex When performed as described here, the tail–flick test is a reliable and useful test of nociception in rodents.

References Tampa Scale for Kinesiophobia 1. Berge O-G, Garcia-Cabrera I, Hole K (1988) Response Latencies in the Tail–Flick Test Depend on Tail Skin Temperature. Neurosci Lett 86:284–288 Synonyms 2. Carstens E, Douglass DK (1995) Midbrain Suppression of Limb Withdrawal and Tail–Flick Reflexes in the Rat: Correlates with TSK Descending Inhibition of Sacral Spinal Neurons. J Neurophys- iol 73:2179–2194 3. D’Amour FE, Smith DL (1941) A Method for Determining Loss Definition T of Pain Sensation. J Pharmacol Exp Ther 72:74–79 4. Duggan AW, Griersmith BT, Headley PM, Maher JB (1978) The The Tampa Scale for Kinesiophobia is a questionnaire Need to Control Skin Temperature when Using Radiant Heat in aimedattheassessmentoffearof(re)injuryduetomove- Tests of Analgesia. Exp Neurol 61:471–478 ment, consisting of 17 items with 4–point likert-scales. 5. Eide PK, Berge O-G, Tjølsen A, Hole K (1988) Apparent  Hyperalgesia in the Mouse Tail–Flick Test due to Increased Tail Disability, Fear of Movement Skin Temperature after Lesioning of Serotonergic Pathways. Acta Physiol Scand 134:413–420 6. Haws CM, Heinricher MM, Fields HL (1990) α-Adrenergic Re- ceptor Agonists, but not Antagonists, Alter the Tail–Flick La- tency when Microinjected into the Rostral Ventromedial Medulla of the Lightly Anesthetized Rat. Brain Res 533:192–195 Tapotement 7. Hole K, Tjølsen A (1993) The Tail–Flick and Formalin Tests in Rodents: Changes in Skin Temperature as a Confounding Factor. Pain 53:247–254  8. Le Bars D, Gozariu M, Cadden SW (2001) Animal Models of Massage and Pain Relief Prospects Nociception. Pharmacol Rev 53:597–652 9. Milne RJ, Gamble GD (1989) Habituation to Sham Testing Pro- cedures Modifies Tail–Flick Latencies: Effects on Nociception rather than Vasomotor Tone. Pain 39:103–107 10. Ren MF, Han JS (1979) Rat Tail–Flick Acupuncture Analgesia Model. Chin Med J 92:576–582 Targeting 11. Roane DS, Bounds JK, Ang C-Y, Adloo AA (1998) Quinpirole- Induced Alterations of Tail Temperature Appear as Hyperalgesia in the Radiant Heat Tail–Flick Test. Pharmacol Biochem Be- hav 59:77–82  Trafficking and Localization of Ion Channels 2396 Tarsal Tunnel

Tarsal Tunnel Task Force on Vicarious Instigation

Definition Definition The anatomic structures that the tibial nerve passes Vicarious instigation describes the phenomenon that, through at the medial ankle are termed the tarsal tun- possibly mediated by empathy, mere observation of nel. Within this tunnel, the tibial nerve divides into the another person’s response to a stimulus or a situation medial and lateral plantar and the calcaneal nerves, (e.g. a pain response) can induce a similar response in each of which has its own separate tunnel as it goes the observer in the absence of any direct experience from the ankle to its final destination. These tunnels with the eliciting stimulus or situation. In the context represent sites of anatomic narrowing in which nerves of pain, it is still a matter of debate whether observing can become entrapped, and which can give symptoms another person in pain can induce a pain-like vicarious of chronic nerve compression in the foot. These can be response in the observer or whether it elicits a more present in the patient with a systemic neuropathy, such generalized emotional response in the observer. as that due to diabetes.  Modeling, Social Learning in Pain  Painful Scars  Ulceration, Prevention by Nerve Decompression

TAUT Task Force on Promotion and Dissemination of Psychological Definition Procedures TAUT is a plasma membrane GABA transporter, which transports taurin with higher affinity than GABA. Definition  GABA and Glycine in Spinal Nociceptive Processing In 1993, Division 12 (ClinicalPsychology) of the Amer- ican Psychological Association appointed a Task Force, with the goal of identifying and disseminating psycho- logical interventions that could be considered as empir- Taut Band ically validated. In its 1995 report, this Task Force pub- lished criteria that allowed the classification of psycho- Definition logical treatments as “well-established” and “probably efficacious” In 1999, for its special issue on empirically A taut band is a string- or cord-like structure in striated validatedtreatmentsinpediatricpsychology,theJournal muscle that extends the length of the muscle fibers. It of Pediatric Psychology defined an additional category consists of a number of fascicles that are most palpable of “promising interventions” A treatment was consid- across(atarightangleto) thefiber directionin theregion eredtobewell-establishediftherewereatleasttwogood of fiber midpoints, where the myofascial trigger point is between-group design experiments (or well-controlled located.Thetautbandistheresponsivepartofthemuscle single case studies) by atleasttwo differentinvestigators in a local twitch response. that demonstrated the treatment’s efficacy over placebo,  Myofascial Trigger Points or at least equal efficacy as compared to an already es- tablished treatment. In addition, a treatment manual or a well defined treatment protocol needed to be available. A treatment was considered as “probably efficacious” if Taxonomy therewereatleasttwoexperimentsshowingitssuperior- ity to a wait-list control, or if there was at least one study NIKOLAI BOGDUK (or a small series of single-case designs) that met the Royal Newcastle Hospital, Department of Clinical well-established treatment criteria. Finally, an interven- Research, University of Newcastle, Newcastle, NSW, tion wasconsidered “promising” if there wasatleastone Australia well-controlledandanotherlesswellcontrolledstudyby [email protected] separate investigators, or a small number of single case experiments, or at least two well-controlled studies by Synonyms the same investigator.  Modeling, Social Learning in Pain Classification; Catalogue; List of Diagnoses and their  Psychological Treatment of Pain in Children Definitions Taxonomy 2397

Definition chronicpain,andprovideddefiningdescriptionsofeach. A  taxonomy is a catalogue that lists and classifies en- Itallowedeachconditiontobedescribedalongfiveaxes: tities and provides definitions of them. It is like a dic- The axis system, however, pertained mainly to the six- tionary restricted to a particular field of scholarship. It digit alphanumeric code ascribed to each condition. The is designed to standardize the meaning and use of par- conditions themselves were classified largely according ticular terms. In relation to pain medicine, a taxonomy to Axis I, with only parenthetical mention of pathology, lists, classifies, and defines terms used to describe pain, aetiology and other features, if these were known. and provides criteria for the use of diagnostic labels. The first edition of the Taxonomy was not intended to be, or expected to be, comprehensive or fixed. Indeed, Characteristics readerswereinvitedtosubmitrevisions(Merskey1986). Two taxonomies have been produced for use in pain The second edition of the Taxonomy (Merskey and medicine. One, developed by the International Associa- Bogduk 1994) addressed many of the shortcomings of tion for the Study of Pain (IASP), covers pain in general the first edition. Some descriptions were modernized,  (Merskey and Bogduk 1994). The other, developed by and involved a name change, e.g. Reflex Sympathetic   the International Headache Society, relates exclusively Dystrophy and causalgia became complex regional to headache (Headache Classification Subcommittee pain syndrome Type I and Type II. Some entries were of the International Headache Society 2004). A related deleted (e.g. prolapsed disc, osteophyte, spondylolysis, taxonomy – the Diagnostic and Statistical Manual of arachnoiditis, acute low back strain, recurrent low back Mental Disorders ( DSM, DSM-IV, DSM-IVR), was strain, and chronic mechanical low back pain) and were developed by the American Psychiatric Association replaced by more generic or alternative entries. Some and is designed to cover mental disorders, but includes new entries were added, e.g. cervicogenic headache, some entries that potentially relate to pain (American xiphoidalgia, carcinoma of the lung, proctalgia fugax, Psychiatric Association 2000). piriformis syndrome, and peroneal muscular atrophy. The greatest revision pertained to entries on spinal pain. IASP Taxonomy Some 96 new entries replaced all previous entries on The taxonomy of the IASP (Merskey and Bogduk 1994) neck pain, back pain, and other spinal pain. Moreover, consists of a short, introductory section devoted to the the new entries were systematic and rigorous. They definition of terms used to describe pain, its different were designed to eliminate the problems of content forms, (such as  somatic pain,  Visceral Nociception validity and of former entries. and Pain,  referred pain,and radicular pain), and The new entries covered standard conditions such as its associated clinical features, such as  hyperalgesia, spinal pain attributable to tumour, infection, metabolic  allodynia,and hyperpathia). The longer, more disease, and arthritis. Radicular pain, due to osteophyte, substantive section lists various entities that constitute disc prolapse, cysts, tumours, etc, was strictly distin- possible diagnoses for patients with  chronic pain. guished and segregated from spinal pain on the grounds For each entity, criteria for making the  diagnosis that, although radicular pain might have a spinal aeti- are stipulated. The entities are catalogued and listed ology, it was pain perceived in the limbs or trunk wall according to the region of the body that they affect. rather than in the spinal region. T Conditions that affect the whole body, or which may Perhaps the most comprehensive change was the intro- occur in any region of the body, are described first, duction of the rubric – “spinal pain of unknown origin”. followed by conditions that affect the head, the neck Users were invited, if not directed, to use this rubric and cervical spine, the upper limbs, the thoracic region wherever an alternative could not be legitimately, or and thoracic spine, the abdomen and pelvis, the lumbar honestly, applied. Providing this rubric encouraged spine, and the lower limbs. physicians to avoid other poorly defined, invalid, or The IASP Taxonomywas developed because it was rec- arbitrary rubrics, in an effort to reduce confusion and ognized thatparticular termswere beingused indiscrim- false labelling of patients. inately by practitioners. Different practitioners were us- Nevertheless, other rubrics were offered. They cov- ing the same term to apply to different conditions, and ered emerging entities, such as discogenic pain and different terms were used to apply to the same condition. zygapophysial joint pain, as well as classical entities, Practitioners were also applying different diagnostic la- such as ligament strain and muscle strain, and allopathic bels to what were essentially the same patients, or were entities such as segmental dysfunction. In providing applying labels to patients that were not appropriate. In these entries, however, the Taxonomy stipulated strin- effect, the use of terms and diagnostic labels was arbi- gent, essential diagnostic criteria, in order to avoid trary. In 1979, Bonica likened the terminology for pain the rubrics being applied on intuitive or presumptive syndromes in use at that time to the “tower of Babel” grounds. (Bonica 1979). Thus, for “ligament strain” the ligament had to be spec- The first edition of the Taxonomy of the IASP (Merskey ified, and the diagnosis had to be proven with a test that 1986)listedcommonandrareconditionsassociatedwith explicitly showed that the ligament in question was the 2398 Taxonomy, Orofacial Pain

Taxonomy, Table 1 Taxonomy

Axis I Region Referred to the anatomical region in which the pain was perceived (e.g., head, abdomen, lower limb).

Axis II System Referred to the body system that ostensibly was affected by pathology to produce pain (e.g. nervous system, vascular system, musculoskeletal system

Axis II Temporal Described whether the pain was continuous, recurring, paroxysmal, etc.

Axis IV Intensity and Stated if the pain was mild, medium or severe; and lasted less than one month, between one and six months, Duration or longer than six months.

Axis V Aetiology Stated the nature of the cause of the pain (e.g. infectious, inflammatory, and neuropathic). source of pain. Similar criteria were applied for “muscle 2. Bonica JJ (1979) The Need for a Taxonomy. Pain 6:247–252 strain”. For “segmental dysfunction” the essential crite- 3. Headache Classification Subcommittee of the International ria required clinical tests of proven reliability, and estab- Headache Society (2004) The International Classification of Headache Disorders, 2nd edn. Cephalalgia 24 Suppl 1:1–160 lished validity to implicate the specified segment as the 4. Merskey H (ed) (1986) Classification of Chronic Pain. Descrip- source of pain. tions of Chronic Pain Syndromes and Definition of Pain Terms. Theserigorouscriteriawerestipulatedquitedeliberately Pain Suppl 3:S1–S225 in the full knowledge that the tests required to make the 5. Merskey H, Bogduk N (1994) Classification of Pain. Descriptions nd diagnosis did not (yet) exist. In effect, therefore, it was of Chronic Pain Syndromes and Definitions of Pain Terms, 2 edn. International Association for the Study of Pain, Seattle, pp impossible to make the diagnosis in practice; yet it ap- 64–65 peared in the Taxonomy. The purpose of this action was 6. Olesen J, Tfelt-Hansen P, Welch KM (2000) The Headaches, 2nd to indicate to proponents of specific, but ill–defined, yet edn. Lippincott Williams & Wilkins, Philadelphia perhapspopular,diagnoses,thatresearchwasrequiredin order for the entity to satisfy the standards of a responsi- ble Taxonomy, and for the diagnosis to be reliable, valid Taxonomy, Orofacial Pain and, therefore, respectable. IHS Taxonomy  Orofacial Pain, Taxonomy/Classification The taxonomy for headache catalogues the many forms of  headache according to mechanism or cause. Diag- nostic criteria are stipulated for each form of headache. These are designed to ensure that practitioners use a par- TCAs ticulardiagnosticlabelonlyinthosepatientswhoexhibit the prescribed criteria.  Tricyclic Antidepressants The taxonomy describes and defines those headaches whose mechanism is not known but which have well- defined clinical features, such as  migraine,  cluster headache,and paroxysmal hemicrania. It contin- TCD ues with descriptions and definitions of headaches associated with particular circumstances (such as the  Thalamocortical Dysrhythmia headaches of analgesic abuse, and rebound headache), headaches due to particular causes (such as raised or lowered pressure of cerebrospinal fluid, cerebral tu- mours, aneurysms, infections and granulomas), and Team Approach headaches associated with other disorders (such as disorders of the ear, nose, and throat, or the cervical  PhysicalMedicineandRehabilitation,Team-Oriented  spine) (see essay headache). Approach Theheadachetaxonomyiscomplementedbyatextbook, nowinitssecondedition(Olesenetal.2000),withathird edition in preparation. The textbook follows the format of the taxonomy, but provides descriptions, in detail, of Technique of Ultrasound Application the entities and their diagnosis and treatment. References Definition 1. American Psychiatric Association (2000) DSM-IV-TR. Diagnos- The most common technique is the stroking technique.  tic and Statistical Manual of Mental Disorders, 4th edn, Text UltrasoundTherapyofPainfromtheMusculoskeletal Revision. American Psychiatric Association, Washington DC System Temporomandibular Joint 2399

Tegretol Temporal Resolution

Synonyms Definition Generic carbamazepine The value indicates how reliable the results are in terms of the time period. The higher, the better, and EEG and Definition MEG are much higher than fMRI and PET. Tegretol (Generic Carbamazepine) is an anti-epileptic  Magnetoencephalography in Assessment of Pain in drug acting at non-voltage dependent sodium channels, Humans which is so effective in the treatment of cranial neural- giasthatlackofa(atleasttransient)responsetothismed- ication raises a significant question about the diagnosis. Temporal Summation (Windup)  Trigeminal, Glossopharyngeal, and Geniculate Neu- ralgias Definition When synaptic potentials overlap in time, they add to- gether. In this case, repeated administration of the same Telemetric stimulus, at a given interval of time, produces a progres- sively increased painful response. Temporal summation Definition is probably the initial part of wind-up, which is the in- Telemetric means the transmission of data by radio or creased neuronal firing to a train of stimuli recorded in other means from a remote source. animals.  Opioid Therapy in Cancer Pain Management, Route  Encoding of Noxious Information in the Spinal Cord of Administration  Exogenous Muscle Pain  Opioids and Muscle Pain  Opioids, Effects of Systemic Morphine on Evoked Temperament Pain  Pain in Humans, Electrical Stimulation (Skin, Muscle  Personality and Pain and Viscera)

Temporal Arteritis Temporomandibular Disorder

Definition Synonyms TMD Temporal arteritis is an arterial disease with inflam- T mation of the temporal arteries characterized by fever, Definition anorexia, loss of weight, leukocytosis, and tenderness over the scalp and along the temporal vessels. The giant A collective term embracing a number of clinical prob- cell arteritis most often attacks the external arteries in lems that involve the masticatory musculature, the tem- the anterior skull region – branches from the arteria poromandibularjoint and associated structures, or both. cerebri externa. Temporomandibular disorders have been identified as a  Cancer Pain, Assessment in the Cognitively Impaired major cause of nondental pain in the orofacial region,  Muscle Pain in Systemic Inflammation (Polymyalgia and are considered to be a subclassification of muscu- Rheumatica, Giant Cell Arteritis, Rheumatoid Arthri- loskeletal disorders. tis)  Orofacial Pain, Movement Disorders  Orofacial Pain, Taxonomy/Classification  Psychological Aspects of Pain in Women Temporal Association

Definition Temporomandibular Joint Temporal association between two disorders or clinical problems refers to their hypothesized relationship in Definition terms of time of onset, most often inferring a causal or The jaw joint. The joint formed between the condylar contributory relationship. process of the mandible and the mandibular fossa and  Depression and Pain articular tubercle of the temporal bone. 2400 Temporomandibular Joint and Muscle Pain Dysfunction

 Nociceptors in the Orofacial Region (Temporo- mandibular Joint and Masseter Muscle)  Psychiatric Aspects of Pain and Dentistry  Temporomandibular Joint Disorders

Temporomandibular Joint and Muscle Pain Dysfunction

 Temporomandibular Joint Disorders

Temporomandibular Joint Disorders

CHRISTIAN S. STOHLER Temporomandibular Joint Disorders, Figure 1 Etiological construct. Baltimore College of Dental Surgery, University of Maryland, Baltimore, MD, USA of association between occlusal features and TMJDs, [email protected] inconsistent findings from study to study regarding the role of a given occlusal attribute, and the absence of Synonyms any gradient effect of occlusal factors put these earlier Temporomandibular joint disorders (TMJDs); Tem- theories in question. poromandibular disorders (TMDs); Craniomandibular Case Assignment Disorders; Previously used diagnostic labels; Tem- Although research in this subject matter has been in- poromandibular Joint and Muscle Pain Dysfunction; tensified in recent years, no biomarkers of exposure or TMJD effect are established for valid and reliable TMJD case ascertainment. TMJD case assignment occurs on the Definition basis of clinical features, which consist of symptoms Temporomandibular disorders (TMJDs) comprise of a like pain and limited range of mandibular motion. Fa- family of musculoskeletal conditions that involve deep cial pain reports focus on anatomical regions such as acheorpainintheareaofthetemporomandibularjoint(s) the temples, cheeks, pre-auricular area, or inside the and/ or adjacent tissue structures. These conditions con- ear and vary in intensity and spatial distribution, both stitute a major source of non-dental pain in the cranio- inter-individually and intra-individually, with time. facial complex. With respect to corresponding clinical signs, allody- nia in the form of tenderness to palpation is linked to Characteristics painful topographical sites. Limited range of motion is often noted and attributed to factors such as the ar- Etiology and Pathogenesis ticular disc preventing smooth gliding movement of Although the etiology of these musculoskeletal pain the mandibular condyle along the articular eminence, disorders is not established and various pathogenetic constraining mandibular excursion, and/ or the recruit- constructs have been proposed, these conditions are ment of jaw closing muscles during their function as believed to develop from the combined action of many antagonists, limiting mandibular side-to-side excur- genes, risk-conferring behaviors and environmental sions and the capacity to open the jaw fully. However, factors. The fact that pain originates in deep tissue under no circumstances should observable signs be appears to be relevant to understanding the clinical used in isolation to define a TMJD case, because of phenomenon because, unlike superficial pain, deep insufficient diagnostic validity due to high sensitivity pain is poorly localized and frequently associated with and low specificity. pronounced autonomic reactions. Genetic vulnerability is attributed to differences in the genetic makeup that Classification Systems enhance, directly or indirectly, pro-nociceptive and/ or Importantindirectingclinicalresearchinthepastdecade attenuate anti-nociceptive signalling (Fig. 1). wereeffortsto produceadualaxestaxonomy for thema- Earlier etiological constructs have placed significant jor types of TMJDs (Dworkin and LeResche 1992). Fo- weight on the dental occlusion as a causal factor in the cusing on the craniofacial domain, Axis I distinguishes etio-pathogenesis of TMJDs. However, low strengths three main diagnostic subsets (Fig. 2): Temporomandibular Joint Disorders 2401

Temporomandibular Joint Disorders, Figure 2 Overview of the diagnostic construct adopted by the Research Diagnostic Criteria for temporomandibular disorders. (For detail see Dworkin and LeResche 1992).

Temporomandibular Joint Disorders, Figure 3 Overlap of TMJDs with regional and systemic disorders.

1. Group I: Masticatory myofascial pain forms of TMJDs. The sensory experience is captured 2. Group II: TMJ internal derangements by pain descriptors, such as “aching”, “tight”, “throb- T 3. Group III: TMJ arthritides bing” and “tender” (Turp et al. 1997). Besides pain, (a) AxisIIcriteriaassesspainintensity,pain-relateddisabil- inability to freely move the jaw due to pain and/ or soft ity, and the presence and severity of depressive and anx- or hard tissue interference, (b) sounds originating from iety symptoms. Using this classification scheme, about the jaw joint, and (c) the disturbing perception of teeth half of allTMJD casesare identifiedasGroupIdisorders not fitting properly constitute the other shared concerns. (List and Dworkin 1996). With respect to clinically observable signs, pressure Due to the overlap with regional myofascial pain, allodynia, the experience of pain in response to defined tension-type headache, fibromyalgia, polyarthritides pressure that is rarely identified as painful by subjects and possibly connective tissue disorders with impaired without TMJDs, represents the clinical hallmark fea- collagen makeup, shortcomings of available TMJD tax- ture of this family of pain conditions. Inability to move onomies are becoming increasingly recognized (Fig. 3). the jaw freely is determined by measurements of the The fact that persistent TMJDs are rarely limited to a mandibular range of motion and expressed by the clini- single topographical domain underscores the need to cally observable maximum mandibular excursions in all assess these conditions in the broader context. directions. Joint sounds are often linked to mechanical events between moving articular structures, such as the temporal component of the TMJ, the articular disc and Phenomenology the condyle. With respect to age, prevalence rates are General Characteristics lower among older subjects, and initial care-seeking in Poorly localizable ache or pain unrelated to dental both men and women is more likely to occur before age pathology, constitute the chief complaint of all major 50 than later in life. 2402 Temporomandibular Joint Disorders

Temporomandibular Joint Disorders, Figure 4 Cases (in %) reporting pain in a given dermatome. Adapted from (Turp, Kowalski, O’Leary, and Stohler, 1998).

Spatial Characteristics phenomenological point of view, it needs to be em- Notonly can temporomandibular joint(TMJ) arthridites phasized that the overwhelming case majority seen in be part of an existing polyarthritis that affects additional the primary care setting exhibits episodic forms, while joints other than the TMJs, those TMJDs that involve cases encountered in the tertiary care environment are muscle differ in the extent of their bodily involvement as more likely affected by persistent conditions. The fact well. Distinction of local and widespread phenomena is that the personally most devastating and clinically most important, because cases with widespread pain are more challenging TMJD presentations occur in females in likely in pain on follow-up examination than cases with greater numbers than males, results in up to 90% of localized pain (Raphael et al. 2000). tertiary care cases being women (Figure 5). Among IncontrasttoTMJD,musclepainconditionsthatinvolve women, prevalence rates are higher for subjects of the face and adjacent head or neck regions, fibromyalgia reproductive age than those in postmenopausal years (FMS) is understood as a clinical entity characterized by without hormone replacement therapy (LeResche et al. persistentwidespreadpainandtendernessto4kilograms 1997). of pressure at 11 of 18 anatomically defined body sites TMJD pain is characterized as non-progressive and (Wolfe et al. 1990). Overlap between TMJDs and FMS fluctuating in intensity, which is often translated into has been demonstrated in a number of studies (Plesh et “good” and “bad” days. What is applicable to a wide al. 1996; Hedenberg- Magnusson et al. 1997; Korszun range of pain disorders seems also to be the case for et al. 1998). According to Plesh and coworkers, 75% of TMJDs. As a generalization, infrequent pains of even their FMS patientshad TMJDs, while, on the other hand, high intensity are more likely perceived as a nuisance 18% of cases with TMJDs met the diagnostic criteria when compared to persistent pain of lesser intensity. for FMS. Epidemiological studies also report high as- On the other hand, persistent pain disrupts the lifestyle, sociations between TMJDs and the two most common causing functional limitations and restrictions in daily types of headache, tension-type headache and migraine activities. In this context, it is increasingly understood headache (Agerberg and Carlsson 1973). In fact, per- that time in pain influences the subject’s physiological sistent TMJD pain is associated with co-morbid pain in state and response behavior. Initial pain constitutes a body parts other than the face at much greater rates than warning signal, causing the subject to stop the ongoing the condition is limited to the face (Fig. 4) (Turp et al. activity and to take actions to alleviate the pain. If pain 1998). persists, longer lasting effects on neuronal excitability, such as the up-regulation of NMDA-mediated effects Temporal Characteristics and changes in the CNS “hardwiring” occur via a series Complaints of pain range from a local response to of events and involve alterations in intermediate and simple injury to complaints of persistent widespread late gene expressions. Binding of c-fos and c-jun to bodily involvement without obvious cause. From a DNA alters the transcription of intermediate and even- Temporomandibular Joint Disorders 2403

Temporomandibular Joint Disorders, Figure 5 Comorbid conditions and male-to-female ratios in different observational settings. tually late effector genes, which in turn affect enzymes, and diet counselling to mention the most common growth factors, peptides, and even the phenotype. interventions. There are little differences among the various types with respect to symptom relief. Those Pain Affect patients that do not get a satisfactory outcome, which Prolonged and persistent pain can induce significant happen to constitute a clear case minority in the primary pain affect, which in itself constitutes an integral part care setting, are characterized by persistent pain and of the TMJDs. Pain affect is captured by pain descrip- dysfunction for which all current forms of treatment tors, such as “tiring”, “exhausting”, “frightening” and fall short. Given the questionable superiority of one “fearful”. Great variations are observed with respect type of intervention over another, the choice of care to the degree to which pain affect is expressed from is more influenced by unwanted effects attributable to patient to patient, even within a given TMJD subset the intervention, and/or the greater cost for care that (Ohrbach and Dworkin 1998). Much of the variability does not translate into a justifiable improvement of the in response to pain is believed to be of genetic origin. therapeutic efficacy. Consequently, case management Consequently, intense research is beginning to iden- tends to be “conservative” and “reversible”. T tify the allelic variants that underlie these response differences. For example, a 3- to 4-fold reduction in References the activity due to a valine-methionine polymorphism 1. Agerberg G, Carlsson GE (1973) Functional Disorders of the of catechol-O-methyltransferase (COMT), an enzyme Masticatory System. II. Symptoms in Relation to Impaired Mo- that catalyzes the O-methylation of compounds with a bility of the Mandible as Judged from Investigation by Ques- catechol structure, results in less or greater than normal tionnaire. Acta Odontol Scand 31:337–347 availability of catecholamines at the site of neurotrans- 2. Dworkin SF, LeResche L (1992) Research Diagnostic Criteria for Temporomandibular Disorders: Review, Criteria, Examinations mission, which in turn significantly shapes the sensory and Specifications, Critique. J Craniomandib Disord 6:301–355 and affective experience of facial pain (Zubieta et al. 3. Hagberg C, Hagberg M, Kopp S (1994) Musculoskeletal 2003). Symptoms and Psychosocial Factors Among Patients with Craniomandibular Disorders. Acta Odontol Scand 52:170–177 Management 4. Hedenberg-Magnusson B, Ernberg M, Kopp S (1997) Symptoms and Signs of Temporomandibular Disorders in Patients with Fi- Because the causal sequence of events that leads to bromyalgia and Local Myalgia of the Temporomandibular Sys- pain and dysfunction is not known, therapeutic inter- tem. A comparative study. Acta Odontol Scand 55:344–349 ventions focus on symptom management rather than on 5. Korszun A, Papadopoulos E, Demitrack M, Engleberg C, Crof- ford L (1998) The Relationship Between Temporomandibular the elimination of the cause. Patients who seek care for Disorders and Stress-Associated Syndromes. Oral Surg Oral Med the first time, report symptom relief of TMJD by 65- Oral Pathol Oral Radiol Endod 86:416–420 95%. Treatments include thermal packs, non-steroidal 6. LeResche L, Saunders K, Von KM, Barlow W, Dworkin SF anti-inflammatory drugs (NSAIDs) and/or muscle re- (1997) Use of Exogenous Hormones and Risk of Temporo- mandibular Disorder Pain. Pain 69:153–160 laxants, inter-occlusal appliances, physical therapy, 7. List T, Dworkin SF (1996) Comparing TMD Diagnoses and Clin- relaxation and stress management, and acupuncture ical Findings at Swedish and US TMD Centers using Research 2404 Temporomandibular Pain

Diagnostic Criteria for Temporomandibular Disorders. J Orofac Characteristics Pain 10:240–253 8. Ohrbach R, Dworkin SF (1998) Five-Year Outcomes in TMD: Anatomy Relationship of Changes in Pain to Changes in Physical and Psy- The anatomic TP sites do not appear to represent a sin- chological Variables. Pain 74:315–326 9. Plesh O, Wolfe F, Lane N (1996) The Relationship Between Fi- gle type of anatomical structure, but rather can include bromyalgia and Temporomandibular Disorders: Prevalence and ligaments, tendons, skeletal muscles and bursae. The Symptom Severity. J Rheumatol 23:1948–1952 TP hurts at the site where pressure is applied, only, 10. Raphael KG, Marbach JJ, Klausner J (2000) Myofascial whereas pain induced by pressure at a myofascial pain Face Pain. Clinical Characteristics of those with Regional vs. Widespread Pain. J Am Dent Assoc 131:161–171 syndrome (MPS) “trigger point“ causes both local pain 11. Turp JC, Kowalski CJ, O’Leary TJ, Stohler CS (1998) Pain Maps and pain at a more distant area of reference (“referred from Facial Pain Patients Indicate a Broad Pain Geography. J Dent pain“). Several efforts have been made to find a pri- Res 77:1465–1472 mary origin of fibromyalgia (FM) pain at the anatomic 12. Turp JC, Kowalski CJ, Stohler CS (1997) Pain Descriptors Char- acteristic of Persistent Facial Pain. J Orofacial Pain 11:285–290 sites themselves (Bengtsson et al. 1986; Drewes et al. 13. Wolfe F (1997) The Relation Between Tender Points and Fi- 1993; Henriksson et al. 1982; Yunus and Kalyan Ra- bromyalgia Symptom Variables: Evidence that Fibromyalgia is man 1989). In fact, most of these investigations studied not a Discrete Disorder in the Clinic. Ann Rheum Dis 56:268–271 skeletal muscle exclusively and did not report any find- 14. Wolfe F, Smythe HA, Yunus MB, Bennett RM, Bombardier C, Goldenberg DL, Tugwell P, Campbell SM, Abeles M, Clark P ings on other anatomical structures composing the TP et al. (1990) The American College of Rheumatology 1990 Cri- regions. Morphological findings in skeletal muscle tis- teria for the Classification of Fibromyalgia. Report of the Mul- sue specimens from FM patients are rather non-specific ticenter Criteria Committee [see comments]. Arthritis Rheum 33:160–172 and presumably secondary to pain-related reduction 15. Zubieta JK, Heitzeg MM, Smith YR, Bueller JA, Xu K, Xu Y, of activity. Results of image analysis quantification of Koeppe RA, Stohler CS, Goldman D (2003) Genotype Affects substance P immunoreactivity in the trapezius mus- Mu-Opioid Neurotransmitter Responses to a Pain Stressor. Sci- cle of patients with fibromyalgia and myofascial pain ence 299:1240–1243 syndrome pointed to a peripheral hyperactivity of the peptidergic nervous system in FM as well as in MPS (De Stefano et al. 2000). Recently reported ultrastructural changes in fibromyalgic muscle fibers may contribute Temporomandibular Pain to the induction and / or chronicity of nociceptive trans- mission from muscle to the central nervous system (Sprott et al. 2004). But, these alterations could not be Definition identified as a primary cause of hyperalgesia in FM TP Chronic pain in the jaw muscles and TM joint, often as- areas. sociated with malocclusion; also referred to as cranio- Clinical Characteristics mandibular or temporo-mandibular dysfunction.  Jaw-Muscle Silent Periods (Exteroceptive Suppres- Application of pressure on each of the TPs often induces sion) patient’s involuntary withdrawal. After the examination of all 18 TPs, patients may report a persisting “deep ache“, similar to that of bone pain. Some patients may show the symptoms with either one half (upper or lower) or one side (right or left) of the body preponderating. Tender Points For standardization and for research purposes, pressure MICHAEL SPAETH gauges are available. A dolorimeter is commonly used Friedrich-Baur-Institute, University of Munich, and can further help to standardize the amount of pres- Munich, Germany sure (e.g. 4 kg) applied by the examining finger of each [email protected] investigator. [email protected] Recent Objections Despite the lack of information on what TPs really do Synonyms measure, research over the last few years has brought up some interesting findings about these points. There TePs is evidence from different studies, that FM patients are Formerly often used as synonymous: trigger points (but tendererinbothTPandnon-TPregionsthanhealthycon- nowadays clearly discriminated) trol subjects and that these TP regions represent areas, where anyone is tenderer. TPs were revealed not to be Definition specific to FM (Granges and Littlejohn 1993b; Tunks et If an individual reports local pain when a site is palpated al. 1995). with standardized pressure, this is considered a positive TPs were studied in a random sample from adults in the “tender point” (TP). general population. As a result, tenderness to pressure Tendon Sheath Inflammation 2405 was found to occur both in people without widespread 6. Gracely RH, Grant MA, Giesecke T (2003) Evoked pain mea- pain and in people without any pain. The investigators suresinfibromyalgia. BestPract ResClin Rheumatol 17:593–609 7. Granges G, Littlejohn G (1993a) Pressure pain threshold in pain- found that TP counts were increased in people who had free subjects, in patients with chronic regional pain syndromes, other symptoms (i.e. poor sleep and / or fatigue), even if and in patients with fibromyalgia syndrome. Arthritis Rheum they did notcomplain aboutpain atall(MacFarlaneetal. 36:642–646 1996). Data suggest that TP counts can discriminate be- 8. Granges G, Littlejohn GO (1993b) A comparative study of clin- ical signs in fibromyalgia / fibrositis syndrome, healthy and ex- tween tender and non-tender individuals and can there- ercising subjects. J Rheumatol 20:344–351 fore be considered as a clinically useful measure of ten- 9. Henriksson KG, Bengtsson A, Larsson J et al. (1982) Muscle derness (Gracely et al. 2003). From another study, it was biopsy findings of possible diagnostic importance in primary fi- concluded that the tender point count was associated not bromyalgia (fibrositis, myofascial syndrome). Lancet 2:1395 10. MacFarlane GJ, Croft PR, Schollum J et al. (1996) Widespread only with the extent of rheumatic pain, but also indepen- pain: is an improved classification possible? J Rheumatol dently with the extent of bodily complaints (Schochat 23:1628–1632 and Raspe 2003). Significant correlations were found 11. McCarberg B, Barkin RL, Wright JA et al. (2003) Tender points between TP count and psychologicaldistress, evaluated as predictors of distress and the pharmacologic management of fibromyalgia syndrome. Am J Ther 10:176–192 by analyzing somatic and depressive symptoms (Croft 12. Petzke F, Gracely RH, Park KM et al. (2003) What do tender et al. 1994). Another study found that TP pain severity pointsmeasure?Influence ofdistresson 4measuresoftenderness. ratings produced higher correlations with symptoms of J Rheumatol 30:567–574 FM and predicted distress better than TP counts (Mc- 13. Schochat T, Raspe H (2003) Elements of fibromyalgia in an open population. Rheumatology (Oxford) 42:829–835 Carberg et al. 2003). 14. Sprott H, Salemi S, Gay RE et al. (2004) Increased DNA fragmen- Since the TP count seems to be a composite measure tation and ultrastructural changes in fibromyalgic muscle fibres. of at least tenderness and psychological distress, it is of Ann Rheum Dis 63:245–251 15. Tunks E, McCain GA, Hart LE et al. (1995) The reliability of ex- limited value in research settings but useful in a clinical amination for tenderness in patients with myofascial pain, chronic setting in order to recognize the tenderness-distress na- fibromyalgia and controls. J Rheumatol 22:944–952 ture of FM (Gracely et al. 2003). Furthermore, the TP 16. Yunus MB, Kalyan Raman UP (1989) Muscle biopsy findings in count does not reflect differences in distress or pressure- primary fibromyalgia and other forms of nonarticular rheuma- pain sensitivity or provide help in subgrouping FM pa- tism. Rheum Dis Clin North Am 15:115–134 tients (Giesecke et al. 2003). Another study replicated previous findings in population-basedsamples showing that dolorimeter determinations are less influenced by Tenderness psychological factors than TP counts (Croft et al. 1994; Granges and Littlejohn 1993a), but there was still an im- Definition pact of distress even on dolorimetry results (Petzke et al. Tenderness describes a feeling of discomfort or pain 2003). caused by pressure that would normally be insufficient Most of these data-based objections were followed by to cause such sensations. recommendations: (1) to re-consider the current defi-  Headache, Episodic Tension Type nition of FM, (2) to be aware of the tenderness-distress nature of both FM and TPs and (3) to re-evaluate chronic T widespread pain (CWP) in further population-based studies both to potentially discriminate between CWP Tendinitis and FM and to emphasize FM characteristics.  Muscle Pain, Fibromyalgia Syndrome (Primary, Sec- Definition ondary) Tendinitusisapainfultendon,usuallyresultingfromun- References accustomed physical activity. Classified as a localized 1. Bengtsson A, Henriksson KG, Larsson J (1986) Muscle biopsy STP. Fraying and thickening of the tendon may be ob- in primary fibromyalgia. Light-microscopical and histochemical served. findings. Scand J Rheumatol 15:1–6  Ergonomics Essay 2. Croft P, Schollum J, Silman A (1994) Population study of  Muscle Pain, Fibromyalgia Syndrome (Primary, Sec- tender point counts and pain as evidence of fibromyalgia. Bmj 309:696–699 ondary) 3. De Stefano R, Selvi E, Villanova M et al. (2000) Image analysis quantification of substance P immunoreactivity in the trapezius muscle of patients with fibromyalgia and myofascial pain syn- drome. J Rheumatol 27:2906–2910 Tendon Sheath Inflammation 4. Drewes AM, Andreasen A, Schroder HD et al. (1993) Pathology of skeletal muscle in fibromyalgia: a histo-immuno-chemical and ultrastructural study. Br J Rheumatol 32:479–483 Definition 5. Giesecke T, Williams DA, Harris RE et al. (2003) Subgrouping of fibromyalgia patients on the basis of pressure-pain thresholds Tendon sheaths have synovial lining cells, which are in- and psychological factors. Arthritis Rheum 48:2916–2922 cluded in the inflammation in rheumatoid arthritis. 2406 Tenosynovitis

 Muscle Pain in Systemic Inflammation (Polymyalgia rate. However, increasing the intensity so as to also ac- Rheumatica, Giant Cell Arteritis, Rheumatoid Arthri- tivate Aδ nociceptors reduces spontaneous activity and tis) responsestonoxiousheatorpinch(Leeetal.1985).Sim- ilarly, studies by Garrison and Foreman (1997) and by Sjolund (1985) both show that increasing intensity in- Tenosynovitis creases inhibition of dorsal horn neurons and the flexion reflex response to noxious stimuli. These data suggest Definition that high and low frequency TENS are effective and that increasing intensity increases inhibition. Tenosynovitis refers to inflammation of the tendon Utilizing an animal model of joint inflammation re- sheaths, through which the tendons slide when the veals that high frequency, sensory intensity TENS has muscle length changes. Excessive fluid accumulation long-lasting effects on both primary and secondary can cause swelling and pain in the affected areas. heat and mechanical  hyperalgesia (reviewed in Sluka  Ergonomics Essay and Walsh 2003) (Fig. 1). In fact, these studies show that high frequency, sensory intensity partially reverses the primary hyperalgesia and completely reverses the TENS secondary hyperalgesia associated with  carrageenan inflammation for 24 h. Importantly, modulation of frequency (4 Hz vs. 100 Hz), intensity (sensory vs.  Transcutaneous Electrical Nerve Stimulation motor) or pulse duration (100 μs vs. 250 μs) shows a frequency, but not intensity or pulse duration, de- pendent effect on primary hyperalgesia to mechanical TENS, Mechanisms of Action and heat stimuli in animals with carrageenan paw in- flammation. The increased responsiveness of dorsal KATHLEEN A. SLUKA Physical Therapy and Rehabilitation Science Graduate horn neurons to innocuous and noxious mechanical stimuli that occurs after inflammation is completely Program, University of Iowa, Iowa City, IA, USA [email protected] reduced following high frequency, sensory intensity TENS treatment applied to the inflamed paw (Ma and  Synonyms Sluka 2001). Utilizing a model of neuropathic pain, Somers and Clemente (1998) demonstrated that high PES; electrical stimulation analgesia; transcutaneous frequency, sensory intensity TENS stimulation over electrical nerve stimulation the paraspinal musculature reduced the heat but not the mechanical hyperalgesia that normally occurs in this Definition model. This inhibition of heat hyperalgesia only occurs Electrical stimulation applied to the skin for pain relief. if TENS was started the first day after injury but not if it was started 3 days after injury. Characteristics The mechanisms of action of  TENS primarily involve Pharmacology centralmechanismsand have been extensively reviewed In animals that were spinalized to remove descending (see Sluka and Walsh 2003 for more details and refer- inhibitory pathways (Fig. 2), inhibition of the tail flick ences). There are generally two types of TENS applied by high frequency, motor intensity TENS still occurs clinically, low frequency (<10 Hz) and high frequency but is reduced by about 50% (Woolf et al. 1980). Thus, (>50 Hz). These can be applied at either a sensory inten- these studies suggest both spinal and  descending sity that produces a tapping or tingling sensation or at inhibition are involved in the analgesia produced by motor intensity that produces an additional motor con- high frequency, motor intensity TENS. Later studies traction. The mechanisms of action for TENS appear to prevented the antihyperalgesia, by blockade of δ-opioid be frequency, not intensity, dependent. receptors in the rostral ventral medial medulla (RVM), further supporting a role for descending inhibitory High Frequency (50–100 Hz) TENS systems in the inhibition produced by TENS. Effects on Behavior and Dorsal Horn Neurons Pharmacologically, opioid peptides mediate the ef- Early studies utilizing acute pain tests show that high fects of high frequency TENS. Concentrations of frequency, motor intensity TENS increases the tail flick beta-endorphins increase in the bloodstream and cere- latency to heat (i.e. analgesia) and decreases the flexion brospinal fluid and methionine-enkephalin increases in reflex response to noxious stimuli (reviewed in Sluka the cerebrospinal fluid of human subjects, following ad- and Walsh 2003). Recording from spinothalamic tract ministration of high frequency, sensory intensity TENS cells, stimulation at an intensity activating Aβ fibers (3 × (reviewed in Sluka and Walsh 2003). High frequency, the threshold) has no effect on the spontaneous firing motor intensity TENS is blocked by systemic block- TENS, Mechanisms of Action 2407

TENS, Mechanisms of Action, Figure 1 Effects of TENS on primary and secondary, mechanical and heat hyperalgesia induced by carrageenan inflammation. High, but not low, frequency TENS partially reverses primary hyperalgesia to heat and mechanical stimuli induced by carrageenan paw inflammation (left panels). In contrast, both high and low frequency TENS reverse secondary hyperalgesia induced by carrageenan knee joint inflammation (right panels).

TENS, Mechanisms of Action, T Figure 2 Schematic drawing demonstrating that TENS applied to the periphery at the site of injury activates primary afferent fibers. This information is transmitted to the spinal cord and results in inhibition both locally and from descending inhibitory pathways. Descending inhibition from the rostral ventral medial medulla (RVM) involves 5-HT and opioids and can be activated by the periaqueductal gray (PAG). Previous studies show that opioid receptors in the spinal cord and RVM and serotoninergic and muscarinic receptors in the spinal cord mediate the reduction in hyperalgesia by TENS. ade of opioid receptors with naloxone and systemic sensory intensity TENS in animals with carrageenan depletion of serotonin (reviewed in Sluka and Walsh knee joint inflammation (Fig. 3) (Kalra et al. 2001; 2003). Blockade of δ-opioid receptors in the spinal Sluka et al. 1999). Similarly, spinal δ-opioid recep- cord or the rostral ventral medial medulla (RVM) re- tors are implicated in the antihyperalgesic effects of verses the antihyperalgesiaproduced by high frequency high frequency motor intensity TENS, since repeated 2408 TENS, Mechanisms of Action

Autonomic and Peripheral Effects TENS could have effects on autonomic function, blood flow and peripheral afferent fibers (reviewed in Sluka and Walsh 2003). However, high frequency, sensory in- tensity TENS stimulation at intensities just above or be- low motor threshold does not affect local blood flow. In contrast, utilizing laser Doppler imaging, increases in blood flow were observed with high frequency TENS, at an intensity “that was felt but not painful (10–15 mA). In human subjects, after application of high frequency TENS at the threshold for discomfort (strong motor in- tensity applied to a digit), subjects report numbness and coolingjustdistaltothestimulation(onthedigit).Thisis associated with decreased temperature and loss of color in the skin suggesting effects on the autonomic nervous system. The primary afferent neuropeptide, substance P, is reduced in dorsal root ganglia neurons and spinal cord dorsal horn by high frequency, sensory intensity TENS in animals injected with the inflammatory irri- tant, formalin. Thus, evidence is beginning to emerge that some of the analgesic effects of TENS may be medi- ated through actions on primary afferent fibers and mod- ulation of autonomic activity.

Low Frequency (<10 Hz) TENS Effects on Behavior and Dorsal Horn Neuron Activity In primates without tissue injury, low rate burst TENS (3 bursts per second and 7 pulses per burst with an in- ternal frequency of 85 Hz) at an intensity that activates Aβ (presumable sensory intensity, 3 × sensory thresh- old) fibers has no effect on either the spontaneous activ- ity or responsesto noxiousstimuliof spinothalamictract cells. Increasing intensity to activate Aδ fibers reduces TENS, Mechanisms of Action, Figure 3 Summary bar graph of the ef- fects of blockade of spinal receptors on the antihyperalgesia produced spontaneousactivity and responsesto noxiousstimuliof by low and high frequency TENS. Approximately 100% inhibition of hy- spinothalamic tractcells(Lee etal. 1985). Similarly,low peralgesia occurs after treatment with either high or low frequency TENS frequency TENS at an intensity that activates Aδ fibers (saline, purple). Blockade of μ-opioid (naloxone, dark blue) and muscarinic (atropine, red) receptors prevents the antihyperalgesia produced by high reducestheventralrootreflexinresponsetoC-fiberstim- frequency TENS. Blockade of spinal δ-opioid (naltrindole, blue), serotonin ulation (Sjolund 1985). (methysergide, green) or muscarinic (atropine, red) receptors prevents the Low frequency TENS, regardless of intensity has no antihyperalgesia produced by low frequency TENS. Spinal blockade of α-2 effect on the primary mechanical or heat hyperalge- adrenergic (yohimbine, yellow) or nicotinic (mecamylamine, orange) recep- tors has no effect on the effects of either high or low frequency TENS. sia produced by carrageenan inflammation. However, low frequency, sensory intensity TENS fully reverses secondary heat hyperalgesia and partially reverses sec- ondary mechanical hyperalgesia (reviewed in Sluka and application of high frequency, motor intensity TENS Walsh 2003). Importantly, in these studies, increasing produces tolerance (reduced effectiveness) to the an- intensity to twice the motor threshold does not further tihyperalgesic effects of TENS and at spinal δ-opioid reduce the secondary mechanical hyperalgesia. The receptors (Chandran and Sluka 2003). increased responsiveness of dorsal horn neurons to Further, blockade of muscarinic receptors (M1 and M3, innocuous and noxious mechanical stimuli that occurs but not M2) in the spinal cord also partially reverses the after inflammation is equally and completely reduced antihyperalgesia produced by high frequency, sensory following low frequency, sensory intensity TENS treat- intensity TENS (Radhakrishnan and Sluka 2003). How- ment applied to the inflamed paw (Ma and Sluka 2001). ever, blockade of serotonin or noradrenergic receptors Following spinal nerve ligation, TENS reduces the in the spinal cord has no effect on the reversal of hyper- responsiveness to noxious mechanical stimulation of algesia produced by high frequency, sensory intensity dorsal horn neurons in both normal and neuropathic TENS (Radhakrishnan et al. 2003) (Fig. 3). animals. However, the responsiveness of spinal neurons TePs 2409 to innocuous mechanical stimulation is only inhibited 8. Radhakrishnan R, Sluka KA (2003) Spinal muscarinic recep- by TENS in neuropathic animals (Leem et al. 1995). tors are activated during low or high frequency TENS -induced antihyperalgesia in rats. Neuropharmacology 45:1111–1119 Behaviorally, low frequency, motor intensity TENS 9. Radhakrishnan R, King EW, Dickman J et al. (2003) Spinal reduces mechanical hyperalgesia and cold allodynia 5-HT(2) and 5-HT(3) receptors mediate low, but not high, induced by nerve injury (Nam et al. 2001). frequency TENS-induced antihyperalgesia in rats. Pain 105:205–213 Pharmacology 10. Sherry JE, Oehrlein KM, Hegge KS et al. (2001) Effect of burst- mode transcutaneous electrical nerve stimulation on peripheral Low frequency,sensory intensity, TENS antihyperalge- vascular resistance. Phys Ther 81:1183–1191 sia is prevented by blockade of μ-opioid receptors in the 11. Sjolund BH (1985) Peripheral nerve stimulation suppression of spinal cord or the RVM (Fig. 3) (Kalra et al. 2001; Sluka C-fiber evoked flexion reflex in rats. Part 1: Parameters of con- et al. 1999). Studies utilizing carrageenan knee joint in- tinuous stimulation. J Neurosurg 63:612–616 μ 12. Sluka KA, Walsh D (2003) Transcutaneous electrical nerve stim- flammationsuggestthat -opioidreceptorsarealsoacti- ulation: Basic science mechanisms and clinical effectiveness. J vated by low frequency, motor intensity TENS since re- Pain 4:109–121 peatedapplicationofTENSproducestolerance(reduced 13. Sluka KA, Deacon M, Stibal A et al. (1999) Spinal blockade of effectiveness) to the antihyperalgesic effects of TENS opioid receptors prevents the analgesia produced by TENS in μ arthritic rats. J Pharmacol Exp Ther 289:840–846 and of spinal -opioid receptors (Chandran et al. 2003). 14. Somers DL Clemente FR (1998) High-frequency transcutaneous Low frequency, sensory intensity TENS is also reduced electrical nerve stimulation alters thermal but not mechanical by blockade of serotonin 5-HT2A and 5-HT3 and mus- allodynia following chronic constriction injury of the rat sciatic carinic M1 and M3 receptors in the spinal cord (Fig. 3) nerve. Arch Phys Med Rehabil 79:1370–1376 15. Woolf CJ, Mitchell D, Barrett GD (1980) Antinociceptive ef- (Radhakrishnan et al. 2003; Radhakrishnan and Sluka fect of peripheral segmental electrical stimulation in the rat. Pain 2003).Takentogether,thesestudiessuggestaroleofopi- 8:237–252 oid,serotoninandmuscarinicreceptorsinthespinalcord and supraspinal opioid mechanisms in the action of low frequency, sensory intensity TENS. TENS Outcomes Autonomic Effects of Low Frequency TENS The effect of low frequency, motor intensity TENS on  Transcutaneous Electrical Nerve Stimulation Out- cold allodynia, but not mechanical hyperalgesia, is re- comes duced by systemic phentolamine to block α-adrenergic receptors, suggesting activation of sympathetic nora- drenergic receptors may mediate TENS effects (Nam et Tension Headache al. 2001). However, phentolamine could block central receptors. Transient increases in blood flow with low frequency, burst-mode (2 Hz) TENS were observed at  Headache, Episodic Tension Type the area of stimulation, if intensity was 25% above the motor threshold, but not just below (sensory intensity) or just above motor threshold (Sherry et al. 2001). Tension Type Headache T References 1. Chandran P, Sluka KA (2003) Development of opioid tolerance Definition with repeated TENS administration. Pain 101:195–201 2. Garrison DW, Foreman RD (1997) Effects of prolonged tran- Tension Type Headache in SLE patients is associated scutaneous electrical nerve stimulation (TENS) and variation of with personality changes, emotional conflicts, depres- stimulation variables on dorsal horn cell activity. Eur J Phys Med sion, and higher disease activity scores. In some cases, Rehabil 6:87–94 tension type headache is associated with tonic contrac- 3. Kalra A, Urban MO, Sluka KA (2001) Blockade of opioid re- ceptors in rostral ventral medulla prevents antihyperalgesia pro- tion of the cranial muscles. Many patients with tension duced by transcutaneous electrical nerve stimulation (TENS). J type headache do not exhibit increased EMG activity in Pharmacol Exp Ther 298:257–263 these muscles, but have the feeling of a tight ring around 4. Lee KH, Chung JM, Willis WD (1985) Inhibition of primate the head. spinothalamic tract cells by TENS. J Neurosurg 62:276–287  5. Leem JW, Park ES, Paik KS (1995) Electrophysiological evi- Headache Due to Arteritis dence for the antinociceptive effect of transcutaneous electrical  Headache, Episodic Tension Type nerve stimulation on mechanically evoked responsiveness of dor-  Sensitization of Muscular and Articular Nociceptors sal horn neurons in neuropathic rats. Neurosci Lett 192:197–200 6. Ma YT, Sluka KA (2001) Reduction in inflammation-induced sensitization of dorsal horn neurons by transcutaneous electrical nerve stimulation in anesthetized rats. Exp Brain Res 137:94–102 7. Nam TS, Choi Y, Yeon DS et al. (2001) Differential antinoci- TePs ceptive effect of transcutaneous electrical stimulation on pain behavior sensitive or insensitive to phentolamine in neuropathic rats. Neurosci Lett 301:17–20  Tender Points 2410 Tertiary Gain

 Acute Pain Mechanisms Tertiary Gain  Membrane Stabilizing Drugs  Nociceptors, Action Potentials and Post-Firing Ex- Definition citability Changes Gains sought or obtained by others from a patient’s ill-  Tetrodotoxin ness.  Malingering, Primary and Secondary Gain

Tetrodotoxin (TTX)-Resistant Sodium TES Channel  Transcutaneous Electrical Stimulation Definition Atypeof voltage-gated sodium channelthatisnotinhib- Testosterone itedbythehighlypotentneurotoxin,tetrodotoxin,which is extracted from the puffer fish. Tetrodotoxin (TTX)- Definition resistant sodium channels are found on the membrane of many DRG neurons that have nociceptive response Testosterone is normally produced in the testes in men, properties, and contribute to the excitability of the neu- the ovaries in women, and in the adrenal cortex of both rons and generation of action potentials. men and women. In men, testosterone is primarily re-  IB4-Positive Neurons, Role in Inflammatory Pain sponsible for normal growth and development of male  Nociceptor Generator Potential sex and reproductive organs, including the penis, testi- cles, scrotum, prostate, and seminal vesicles. It facili- tatesthedevelopmentofsecondarymalesexcharacteris- ticssuchasmusculature,bonemass,fatdistribution,hair patterns, laryngeal enlargement, and vocal chord thick- Thalamic Bursting Activity ening. In women, testosterone strengthens bone and en- sures the nipples and clitoris are sensitive to sexual plea- sure.Inbothmenandwomen,normaltestosteronelevels  Burst Activity in Thalamus and Pain maintain energy level, healthy mood, muscle mass, fer-  Thalamic Bursting Activity, Chronic Pain tility,andsexualdesire.Decreasedlevelsoftestosterone, induced by aging, disease, surgery, and medications (in- cludingopioids),leadtolossoflibidoanddecreasedsex- ual function.  Cancer Pain Management, Opioid Side Effects, En- Thalamic Bursting Activity, Chronic Pain docrine Changes and Sexual Dysfunction A.TAGHVA,S.H.PATEL,A.FERNANDEZ, NIRIT WEISS,FRED A. LENZ Tetrodotoxin Department of Neurosurgery, Johns Hopkins Hospital, Baltimore, MD, USA Synonyms fl[email protected] TTX Synonyms Definition Spike bursting Tetrodotoxin (anhydrotetrodotoxin 4–epitetrodotoxin, tetrodonic acid, TTX) is a potent neurotoxin found in the tissues of the puffer fish. It has a complex structure, Definition with the active part of the molecule being a positively Spontaneous thalamic cellular activity is often catego- charged guanidinium moiety. The molecule can block rized as either bursting activity ( spike bursts,burst- sodium channels from the outside (in contradistinc- ing mode) or as tonic firing (tonic mode) (Steriade et tion to clinically used local anesthetic agents that must al. 1990). Many studies have suggested that increased first permeate the neuron and then act from the in-  spike bursting occurs in the thalamus of patients with side). Tetrodotoxin is used by neurophysiologists to chronic pain (Lenz et al. 1994; Lenz et al. 1988; Rinaldi categorize various types of sodium channel. et al. 1991; Jeanmonod et al. 1993; Lenz et al. 1998). Thalamic Bursting Activity, Chronic Pain 2411

Characteristics It has been reported that the number of bursting cells TheThalamicRegionofVcanditsImportanceinPainProcess- per trajectory in patients with movement disorders (con- ing trols) is not different from that in patients with chronic Several lines of evidence demonstrate that the ventral pain. However, there are significant differences between caudal nucleus of the human sensory thalamus ( Vc), the two studies (Lenz et al. 1994; Radhakrishnan et al. the human analog of monkey ventral posterior (VP) 1999) in terms of patient population (spinal cord injury nucleus (Hirai and Jones 1989), is important in human vs mixed chronic pain), location of cells studied (Vc vs pain-signaling pathways. Studies of patients at autopsy anterior and posterior to Vc) and analysis methods (inci- following lesions of the  spinothalamic tract (STT) dence of bursting cells vs bursting parameters). Clearly, show the most dense STT termination in the Vc region the increase in bursting activity demonstrated in the ear- including the posterior and inferior subnuclei of Vc, lier study is more applicable to the region of the princi- suprageniculate and posterior subnuclei (Mehler 1962; pal somatic sensory nucleus of patients with central pain Walker 1943). In monkeys, STT terminations are found from spinal transection (Lenz et al. 1994). in the Vmpo of Craig, which may, by immunohisto- Further support for increased spike bursts occurring chemistry and physiology, have a human analog (Craig in spinal cord transected patients is found in thalamic et al. 1994). recordings from monkeys with thoracic anterolateral cordotomies (Weng et al. 2000). Some of these animals Is Thalamic Functional Mode Altered in Chronic Pain States? showed increased responsiveness to electrocutaneous  Spike bursting activity refers to a particular pattern stimuli and thus may represent a model of central pain of  interspike intervals (ISI) between action potentials, (Vierck 1991). The most pronounced changes in firing such that a  spike burst begins after a relatively long pattern were found in thalamic  multi-receptive cells, ISI and is comprised of a series of action potentials with which respond to both cutaneous brushing and com- short ISIs (typically < 6 ms) (Lenz et al. 1989). There- pressive stimuli with activity that is not graded into the after, the ISIs progressively lengthen so that the cell’s noxious range. In comparison with normal controls, firing decelerates throughout the spike burst. When the multi-receptive cells in the monkeys with cordotomies period of the bursting is completed, the cell is said to fire showed significant increases in the number of bursts in tonic mode when the firing rate is relatively constant occurring spontaneously or in response to brushing or and bursts do not occur. compressive stimuli. The changes in bursting behavior In patients with spinal transection, the highest rate of were widespread, occurring in the thalamic represen- bursting occurs in cells that do not have peripheral tation of upper and lower extremities, both ipsilateral  receptive fields and that are located in the represen- and contralateral to the cordotomy. tation of the anesthetic part of the body. These cells Although there is an increase in spike burst activity in also have the lowest firing rates in the interval between chronic pain states, there does not appear to be a direct bursts (Lenz et al. 1994). The low firing rates suggest relationship between spike burst firing and pain. Spike that these cells have decreased tonic excitatory drive and burstsarealsofoundinthethalamicrepresentationofthe are  hyperpolarized, perhaps due to loss of excitatory monkey upper extremity and of the representation of the input from the  STT (Eaton and Salt 1990; Dougherty arm and leg ipsilateral to the  cordotomy (Weng et al. T et al. 1996). Therefore the available evidence suggests 2000). Pain is not typically experienced in these parts that affected thalamic cells in patients with spinal tran- of the body in patients with thoracic spinal cord tran- section were dominated by spike bursting consistent section or cordotomy (Beric et al. 1988). Spike bursts with membrane hyperpolarization ( 1990; Steriade and are increased in frequency during slow wave sleep in all Llinas 1988; Lenz et al. 1998; Davis et al. 1998). mammals studied (Steriade and Llinas 1988) including Spikeburstingactivityismaximalintheregionposterior man (Zirh et al. 1997). However, such bursting could and inferior to the core nucleus of Vc (Table 4 in Lenz et cause pain if stimulation in the vicinity of the bursting al. 1994). Stimulation in this area evokes the sensation cellproducedthesensationofpain.Thisfindinghasbeen of pain more frequently than does stimulation in the core reported in two recent studies of sensations evoked by of Vc (Lenz et al. 1993; Hassler 1970). Thus, increased stimulation of the region of Vc in patients with chronic spike bursting activity may be correlated with some as- pain secondary to neural injury (Davis et al. 1996; Lenz pects of the abnormal sensations (e.g.  dysesthesia or et al. 1998). pain)thatthesepatientsexperience.However,inpatients Thus, there is evidence from both human and animal with spinal transection, the painful area and the area of studies for a correlation between chronic pain states sensory loss overlap (Lenz et al. 1994). Thus, the burst- and an altered thalamic neuronal action potential firing ing activity might be related to sensory loss, rather than pattern. It appears that there is an increase in spike burst to pain. firing in chronic pain conditions. The exact physiolog- These findings about spike bursting activity in spinal pa- ical relationships that link the pattern of thalamic firing tients have been called into question by a recent study in to the human perception of chronic pain have yet to be patients with chronic pain (Radhakrishnan et al. 1999). elucidated. 2412 Thalamic Neurotransmitters and Neuromodulators

References lamus following chronic lesion of the ventral lateral spinal cord. Neuroscience 101:393-401 1. Beric A, Dimitrijevic MR, Lindblom U (1988) Central dyses- 23. Zirh AT, Lenz FA, Reich SG et al. (1997) Patterns of bursting thesia syndrome in spinal cord injury patients. Pain 34:109–116 occurring in thalamic cells during parkinsonian tremor. Neuro- 2. Craig AD, Bushnell MC, Zhang ET et al. (1994) A thalamic science 83:107–121 nucleus specific for pain and temperature sensation. Nature 372:770–773 3. Davis KD, Kiss ZHT, Luo L et al. (1998) Phantom sensations generated by thalamic microstimulation. Nature 391:385–387 Thalamic Neurotransmitters and 4. Davis KD, Kiss ZHT, Tasker RR et al. (1996) Thalamic stimulation-evoked sensations in chronic pain patients and non- Neuromodulators pain(movementdisorder)patients. JNeurophysiol 75:1026–1037 5. Dougherty PM, Li YJ, Lenz FA et al. (1996) Evidence that ex- KARIN N. WESTLUND,BRIDGET E. HAWKINS citatory amino acids mediate afferent input to the primate so- Department of Anatomy and Neurosciences, University matosensory thalamus. Brain Res 278:267–273 of Texas Medical Branch, Galveston, TX, USA 6. Eaton SA, Salt TE (1990) Thalamic NMDA receptors and nociceptive sensory synaptic transmission. Neurosci Lett [email protected], [email protected] 110:297–302 7. Hassler R (1970) Dichotomy of facial pain conduction in the di- Synonyms encephalon. In: Walker AE (ed) Trigeminal neuralgia. Saunders, Philadelphia, pp 123–138 Signaling Molecules of Thalamic Regions; thala- 8. Hirai T, Jones EG (1989) A new parcellation of the human tha- mic neurotransmitters and neurochemical effector lamus on the basis of histochemical staining. Brain Res Rev 14:1–34 molecules 9. Jeanmonod D, Magnin M, Morel A (1993) Thalamus and neuro- Definition genic pain: physiological, anatomical and clinical data. Neurorep 4:475–478 The thalamus, a heterogeneous structure located in the 10. 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(1994) Characteristics of mitters of the sensory thalamus in the transmission and somatotopic organization and spontaneous neuronal activity in the region of the thalamic principal sensory nucleus in patients generation of what is perceived as “pain” is still largely with spinal cord transection. J Neurophysiol 72:1570–1587 undefined. More recent observations suggest that neu- 13. Lenz FA, Seike M, Richardson RT et al. (1993) Thermal and romodulation occurs throughout the excitatory and the pain sensations evoked by microstimulation in the area of human inhibitory neurocircuitry of the thalamus. It is clear that ventrocaudal nucleus. J Neurophysiol 70:200–212 14. Lenz FA, Zirh AT, Garonzik IM et al. (1998) Neuronal activity thechemicalneuromodulationoccurringinthethalamus in the region of the principle sensory nucleus of human thalamus permits a significantly more important role for the tha- (ventralis caudalis) in patients with pain following amputations. lamus than simply as a “relay station”. Rather, the tha- Neurosci 86:1065–1081 lamus is an integration site where filtering and consoli- 15. Mehler WR (1962) The anatomy of the so-called “pain tract” in man: an analysis of the course and distribution of the ascending dation of sensory information occurs through chemical fibers of the fasciculus anterolateralis. In: French JD, Porter neurotransmission. RW (eds) Basic Research in Paraplegia. Thomas, Springfield, pp 26–55 Characteristics 16. Radhakrishnan V, Tsoukatos J, Davis KD et al. (1999) A com- parison of the burst activity of lateral thalamic neurons in chronic Neuromodulationinthesensorythalamuscanbestbede- pain and non-pain patients. Pain 80:567–575 scribed in terms of whether the neurochemicals are the 17. Rinaldi PC, Young RF, Albe-Fessard DG et al. (1991) Sponta- content of input fibers, intrinsic interneurons or output neous neuronal hyperactivity in the medial and intralaminar tha- lamic nuclei in patients with deafferentation pain. J Neurosurg components (Table 1; Fig. 1). The primary integrative 74:415–421 sitesinthethalamusfornociceptionarelocatedmedially 18. Steriade M, Jones EG, Llinas RR (1990) Thalamic Oscillations andlaterallyintheposteriorthalamus.Theventralposte- and Signaling. Wiley,John & Sons, New York rior lateral thalamus is chiefly responsible for determin- 19. Steriade M, Llinas RR (1988) The functional states of the thalamus and the associated neuronal interplay. Physiol Rev ing the intensity and location of the painful stimulus be- 68:649–742 fore relaying that information to the appropriate higher 20. Vierck CJ (1991) Can mechanisms of central pain syndromes be cortical regions of the brain. The medial thalamus is in- investigated in animal models? In: Casey KL (ed) Pain and central volved with emotional responses to nociceptive input. nervous system disease: the central pain syndromes. Raven Press, New York, pp 129–141 Thalamic Input 21. Walker AE (1943) Central representation of pain. Res Publ Assoc Res Nerv Ment Dis 23:63–85 The primary sources of sensory information pro- 22. Weng HR, Lee JI, Lenz FA, Vierck CJ, Rowland LH, Dougherty vided to the thalamus are the incoming spinothala- PM (2000) Functional plasticity in primate somatosensory tha- mic, spinotrigeminal and medial lemniscal pathways. Thalamic Neurotransmitters and Neuromodulators 2413

Thalamic Neurotransmitters and Neuromodulators, Table 1 Nociceptive Processing in the Thalamus Thalamic Transmitters and Neuromodulators Thalamic Input Spinothalamic Tract and Medial Lemniscus GLU, CCK

Corticothalamic Tract GLU

Central Tegmental Field and Reticular Activation Systems ACH (ChAT), 5-HT, NA, (TH, DBH), CGRP

Input to Intralaminar and Ventral Thalamic nuclei (from hypothalamus, basal telencephalon, and lateral ENK, SOM, CCK, SP, NPY midbrain) Intrinsic Interneurons and Reticular nucleus GABA, ACH, SOM

Thalamic Output Thalamocortical Projections GLU

Thalamoamygdalar Projections CGRP

T

Thalamic Neurotransmitters and Neuromodulators, Figure 1 Sensory input to the thalamus is transmitted by glutamatergic (GLU) spinothalamic (STT), spinal trigeminal (SpV), dorsal column nucleus (DCN) and reticular formation (RF) neurons. The information, modulated by neuropeptides, is relayed to the medial and lateral thalamus (Thal) where it is influenced by intrinsic GABAergic (GABA) interneurons. The integrated information is routed by glutamatergic thalamic projection neurons to sites including the cerebral cortex (CTh) and amygdala. Reciprocal input back to the thalamus from the cortex is also glutamatergic. Abbreviations: ACh, acetylcholine; CCK, cholecystokinin; CRF, corticotrophin releasing factor; Enk, leu- or met-enkephalin; Glu, glutamate; 5-HT, serotonin; NA, norepinephrine; NPY neuropeptide Y; SOM, somatostatin; SP, substance P; VIP, vasoactive intestinal polypeptide. 2414 Thalamic Neurotransmitters and Neuromodulators

Thalamic Neurotransmitters and Neuromodulators, Figure 2 Schematic diagram illustrating the distribution of substance P immunoreactive fibers (dots) and cell somata (stars) in the monkey diencephalon (Jones 1988).

The corticothalamic tract, from cortical areas SI and also believed to contain at least one neuropeptide, such SII, also provides a large contribution of incoming as SP, cholecystokinin (CCK), bombesin, dynorphin, axonal fibers to the thalamus. Glutamate, the classical enkephalin, galanin, corticotrophin releasing hormone excitatory amino acid, is believed to be the primary (CRH) (Fig. 3) and / or vasoactive intestinal polypep- transmitter of these fiber tracts, based on physiological tide (VIP) (Coffield and Miletic 1987; Leah et al. 1988; and anatomical data. In other brain regions, increased Nahin 1988). In fact, some have been shown to con- release of glutamate and activation of neurons by gluta- tain multiple neuropeptides (Ju et al. 1987). Lamina mate is typically enhanced by the modulatory effects of X STT cells have been shown to predominantly con-  neuropeptides, such as substance P (SP), CGRP and tain bombesin, enkephalin, CCK, somatostatin (SOM), vasoactive intestinal polypeptide (VIP). Neuromodula- CRF, neuropeptide Y and SP (Battaglia et al. 1988; tors such as SP are found in abundance and probably Leah et al. 1988). The SP seems to function as a slow function in a similar manner in the sensory thalamus intermediary for transmission of noxious stimuli as (Fig. 2). The neuropeptide content of neuronal terminals well as a fast excitatory neurotransmitter modulator in the thalamus is believed to be partially from thalamic (Battaglia et al. 1988). Most of the terminals staining input sources (Jones 1988). for SP are located in the medial rather than the lateral thalamus (Fig. 2). Enkephalin has also been identi- Spinothalamic Tract fied in spinotrigeminal neurons (Nahin 1988). These Glutamate has been observed in the spinothalamic findings are supported by both tract tracing / immuno- projection neurons by electron microscopy (Westlund cytochemical studies and negative staining after spinal et al. 1992) (Fig. 1). Most spinothalamic neurons are hemisection. Thalamic Neurotransmitters and Neuromodulators 2415

of the activity of reticular nucleus neurons, which, if it persists, can shift reticular nucleus cells into bursting activity. Iontophoresis of norepinephrine or serotonin markedlyactivatesthereticularnucleusneuronsthrough alpha1 and 5-HT2 (and possibly, 5-HT1C) receptors, due to the decrease in resting potassium conductance. The net result is facilitation of single spike activity and marked inhibition of the rhythmic bursting activity nor- mally promoted by the slow release of norepinephrine in this nucleus. It is assumed that these processes are part of the general arousal system throughout the neuraxis in which these transmitters participate. The highest levels of 5-HT7 receptors are found on the intralami- nar and midline thalamic neurons. Stimulation of the raphe nuclei can alter the responses of these neurons to nociceptive input (Goaillard and Vincent 2002). Corticothalamic Input Corticothalamicinputtothethalamusisalsoglutamater- gic since there is dense staining of both glutamate and aspartate in cells in layers IV and III of SI sensory cortex and many of these cortical cells can be double labeled with tract tracers injected into the thalamus (Guiffrida and Rustioni 1988; Rustioni et al. 1988) Only a small populationofneuronsislabeledwithbothglutamateand aspartate. The corticofugal fibers utilizing glutamate as Thalamic Neurotransmittersand Neuromodulators, Figure 3 After flu- the primary neurotransmitter terminate as small endings orescent tracer is injected into the ventral thalamus, spinothalamic tract containing round vesicles primarily contacting fine cal- cells containing peptides such as corticotrophin releasing factor (CRF) can iber(distal)dendritesofthalamicneuronsandarepartic- be identified in the sacral spinal cord, lamina V. The panel labeled VPL illus- trates two cells retrogradely labeled after injection of fluorescent tracer into ularly dense in the reticular nucleus (Guiffrida and Rus- ventral thalamus. Oneofthesecells alsostained for CRF. Scalebar = 15 μm. tioni 1988; McCormick 1992). (Westlund et al., unpublished). Intrinsic Interneurons Medial Lemniscus The inhibitory neurotransmitter, gamma amino butyric acid( GABA),hasbeenwellcharacterizedinthethala- Input to the thalamus from the dorsal column nuclei is mus, particularly in the reticular nucleus of the thalamus less well studied. Neuropeptide CCK content in the ven- where it is the predominant feature (Fig. 5). It has been T tral posterolateral (VPL) nucleus is, however, reduced determined that GABA is present in the interneurons of upon lesion of the contralateral dorsal column nucleus, the ventral posterior thalamus only in carnivorous an- suggesting that this modulator is involved in the relay imals (i.e. present in primates and cats, but not in rats) of sensory information by the medial lemniscus (Jones (Rustioni et al. 1988). Intrinsic substanceP interneurons 1988). have also been described in the thalamus in regions re- Spinoreticular Pathways ceiving spinothalamic tractinputasdemonstrated byan- terograde tracing (Battaglia et al. 1988). Innervation by brainstem cholinergic, serotonergic and noradrenergic neurons is also present in the thalamus Thalamic Output (Jones 1988; Westlund et al. 1990) (Fig. 4). Sparse Information regarding the sensory-discriminative as- innervation by  serotonin fibers from the raphe nu- pect of pain is sent to parts of the cortex involved in cleus and adjacent periaqueductal gray region has been somatosensory processing, such as precisely localized demonstrated by dual labeling in monkeys. Similarly, areas I (SI), II (SII) and area 4, for further site specific in the same studies, norepinephrine was found sparsely association, in order that pain appropriate response innervating the VPL. However, innervation by sero- instructions can be dispatched via the motor systems. tonergic, noradrenergic and  acetylcholine terminals The thalamocortical efferent pathways (Fig. 1) were is found more prominently in the reticular and dorsal identified as glutamate positive neurons with collaterals lateral geniculate nuclei (as reviewed in McCormick to the reticular nucleus (Guiffrida and Rustioni 1988; 1992). The purpose of these classical neurotransmitters as reviewed in McCormick 1992). Thalamic output to in the thalamus remains unclear, though iontophoretic the cortex is activated by glutamate NMDA and non- application of acetylcholine results in marked inhibition NMDA receptors, since specific antagonists applied 2416 Thalamic Neurotransmitters and Neuromodulators

Thalamic Neurotransmitters and Neuromodulators, Figure 4 Transverse sections of the brainstem of a monkey showing retrograde labeling of neurons (FB) after injection of Fast Blue in the ipsilateral ventral posterolateral nucleus of the thalamus, and the distribution of choline acetyltransferase (ChAT)-, tyrosine hydroxylase (TH)- and serotonin (5HT)-immunoreactive cells (Jones 1988). Thalamic Neurotransmitters and Neuromodulators 2417

Thalamic Neurotransmitters and Neuromodulators, Figure 5 (a) Immunocytochemical staining of GABAergic neurons in the reticular nucleus (R) of a cat, identified using antiserum to glutamic acid decarboxylase (GAD). Fine dots in the dorsal thalamus are GAD-positive somata of interneurons. (b) Higher-power photomicrograph of GAD-positive cells in reticular nucleus (R) and ventral posterior (VP) nucleus of a cat. Bars = 1 mm (a), 250 μm (b). (Jones 1985) to the thalamus can block transmission of thalamic movement in thalamic neurons (Liu and Jones 1996). outflow. The glutamatergic input to the thalamocortical The CaM kinase II terminals in the cerebral cortex are neurons probably arises from the input sources detailed thought to be terminals of thalamocortical neurons. above. There is also an affective componentto pain perception, References which contributes to the emotional responses generated 1. Battaglia G, Spreafico R, Rustioni A (1988) Substance P- in response to the stimulus. This aids in memory de- immunoreactive fibers in the thalamus from ascending so- velopment for future avoidance of the painful situation. matosensory pathways. In: Bentivoglio M, Spreafico R (eds) Cellular Thalamic Mechanisms. Elsevier Science Publishers, T These functions are relegated to the mediodorsal (ven- Amsterdam trocaudal) (MDvc) and intralaminar thalamic regions 2. Coffield JA, Miletic V (1987) Immunoreactive enkephalin is con- which receive input mainly from laminae I and X of the tained within some trigeminal and spinal neurons projecting to spinal cord and send projections to the cingulate cortex the rat medial thalamus. Brain Res 425:380–383 3. Goaillard JM, Vincent P (2002) Serotonin suppresses the slow (in primates). The ventral posterior inferior nuclei send afterhyperpolarization in rat intralaminar and midline thalamic signals directly to the somatosensory area of the parietal neurones by activating 5-HT(7) receptors. J Physiol 541:453–465 cortex (SII) and indirectly to the insula (Millan 1999). 4. Guiffrida R, Rustioni A (1988) Glutamate and aspartate im- Both may be joined by additional ipsilateral input. A munoreactivity in corticothalamic neurons of rats. In: Bentivoglio M, Spreafico R (eds) Cellular Thalamic Mechanisms. Elsevier thin layer of CGRP neurons is found just ventral to Science Publishers, Amsterdam, pp 311–320 the thalamus near to the meso-diencephalic junction 5. Jones EG (1985) Transmitters, receptors, and related compounds (Kruger et al. 1988) and is associated with the thala- in the thalamus. In: Jones EG (ed) The Thalamus. Plenum Press, mus and the somatosensory pathways, as are all CGRP New York, pp 225–256 6. Jones EG (1988) Modern views of cellular thalamic mechanisms. components of the nervous system. These CGRP neu- In: Bentivoglio M, Spreafico R, (eds) Cellular Thalamic Mech- rons have been shown to provide a thalamoamygdalar anisms. Elsevier Science Publishers, pp 1–22 projection which may also be important in generating 7. Ju G, Melander T, Ceccatelli S et al. (1987) Immunohisto- chemical evidence for a spinothalamic pathway co-containing the emotional responses to painful stimuli. cholecystokinin- and galanin-like immunoreactivities in the rat. Calcium calmodulin-dependent protein kinase (CaM Neuroscience 20:439–456 kinase II) has been found in thalamic dendrites apposed 8. Kruger L, Sternini C, Brecha NC et al. (1988) The thalamic re- by glutamate terminals, suggesting that this major post- gion of calcitonin gene-related peptide (CGRP) immunoreactiv- ity and its relation to somatosensory pathways. In: Bentivoglio synaptic activity regulator may assist in modulating M, Spreafico R (eds) Cellular Thalamic Mechanisms. Elsevier synaptic strength, transmitter release and / or vesicle Science Publishers, Amsterdam, pp 375–386 2418 Thalamic Nociceptive Neurons

9. Leah J, Menetrey D, de Pommery J (1988) Neuropeptides in Definition long ascending spinal tract cells in the rat: evidence for parallel processing of ascending information. Neuroscience 24:195–207 Nuclei of the dorsal thalamus whose neurons receive 10. Liu XB, Jones EG (1996) Localization of alpha type II calcium inputsfrom ascending nociceptivepathwaysandproject calmodulin-dependent protein kinase at glutamatergic but not to cortical nociceptive areas. The neurons respond to gamma-aminobutyric acid (GABAergic) synapses in thalamus  and cerebral cortex. Proc Natl Acad Sci USA 93:7332–7336 stimulation of nociceptors in skin, muscles, joints 11. McCormick DA (1992) Neurotransmitter actions in the thala- and viscera. The different thalamic regions process mus and cerebral cortex and their role in neuromodulation of and transmit information subserving the  sensory- thalamocortical activity. Prog Neurobiol 39:337–388 discriminative and the  motivational-affective com- 12. Millan MJ (1999) The induction of pain: an integrative review. Prog Neurobiol 57:1–164 ponents of pain. 13. Nahin RL (1988) Immunocytochemical identification of long as- cending, peptidergic lumbar spinal neurons terminating in either Characteristics the medial or lateral thalamus in the rat. Brain Res 443:345–349 14. Rustioni A, Battaglia G, De Biasi S et al (1988) Neuromediators A distinction is generally made in all species between in somatosensory thalamus: an immunocytochemical overview. a lateral and a medial thalamic system, the lateral with In: Bentivoglio M, Spreafico R (eds) Cellular Thalamic Mech- anisms. Elsevier Science Publishers, Amsterdam, pp 271–296 neurons encoding stimulus quality, duration, inten- 15. Westlund KN, Sorkin LS, Ferrington DG, Carlton SM, Willcock- sity and location on the body and thus subserving the son HH, Willis WD (1990) Serotonergic and noradrenergic pro-  sensory-discriminative component of pain,theme- jections to the ventral posterolateral nucleus of monkey thalamus. dial system with neurons activated from large areas J Comp Neurol 295:197–207 16. Westlund KN, Carlton SM, Zhang D et al. (1992) Glutamate- of the body and/or internal organs and involved in the immunoreactive terminals synapse on primate spinothalamic motivational-affective component of pain. The different tract cells. J Comp Neurol 322:519–527 response properties reflect ascending inputs dominated bythespinothalamicandspinaltrigeminothalamictracts (STT) and projection to the SI and SII somatosensory Thalamic Nociceptive Neurons cortices (lateral system) versus STT and spinoreticu- lothalamic tract and widespread cortical projections including limbic areas (medial system).  Human Thalamic Nociceptive Neurons In contrast to other sensory nuclei in the thalamus, no- ciceptive “nuclei” cannot be delineated histologically. Rather, nociceptive neurons are found within nuclei pri- Thalamic Nociceptive System marily subserving other functions like the mediodorsal or intralaminar nuclei or the ventral posterior complex  Thalamic Nuclei Involved in Pain, Cat and Rat (VP). Thus, “thalamic nuclei involved in pain” have been identified by neuroanatomical tracing of termina- tions of ascending tracts carrying nociceptive signals Thalamic Nuclei or by  electrophysiological mapping of neurons re- sponsive to noxious stimuli. The latter is hindered further by the problems of applying painful stimuli in Definition awake animals or the inherent  antinociceptive effects The thalamus, which is located in the centre of the cere- of general anesthetics when studies are done under bral cortex, is comprised of many nuclei. The thalamus  anesthesia (Vahle-Hinz and Detsch 2002; Vahle- relays information to and from the cerebral cortex, and Hinz et al. 2002). At the spinal cord level, the majority also plays a part in modulating sensory information. of nociceptive somatic and visceral neurons in addi-  Central Pain, Diagnosis tion have low-threshold somatic receptive fields (RFs), which may be preserved in the thalamus while their no- ciceptive components are abolished by the anesthetic. Thalamic Nuclei Involved in Pain, Cat and These difficulties are reflected in the heterogeneous Rat picture of thalamic nociception in the literature (for review see Willis 1997) and it still awaits clarification CHRISTIANE VAHLE-HINZ whether species differences originate from princi- Institute of Neurophysiology and Pathophysiology, pally different organizations or a unifying picture may University Hospital Hamburg-Eppendorf, Hamburg, emerge. Germany [email protected] Lateral Thalamus Nociceptiveneuronsarefoundinregionsofterminations Synonyms of the STT that are patchy and dispersed in and around Thalamic Nociceptive System; Lateral and Medial Tha- the VP and the posterior complex (PO) in the rat while lamic Nociceptive System they are confined to the PO and the margins of the VP in Thalamic Nuclei Involved in Pain, Cat and Rat 2419 the cat. These regions are further characterized by small matawithdenseradialdendriticarbors(Fig.1c)(Kniffki neurons and may correspond to the small-celled matrix et al. 1993). regionsinandaroundtheVPofmonkeys.Thus,although Nociceptive neurons occur in the periphery of the VP the location of nociceptive neurons may differ between (VPp) in the cat (Kniffki and Vahle-Hinz 1987; Vahle- species (outside versus inside VP), this may result from Hinz et al. 1987). This peripheral region is character- a different degree of invasion of this small-celled matrix ized by scattered neuronswith small, spindle-shaped so- into the VP. mataandfewprimarydendritesgivingrisetosparseden- dritic arbors oriented within the confines of the region, Region of the Ventral Posterior Complex (VP) i.e. mediolaterally along its borders (Fig. 1c) (Kniffki et The VP is characterized by input from the medial and al. 1993). The narrow sheath of cells wraps around the trigeminal lemnisci carrying a somatotopic representa- VP dorsally and laterally, extending towards the exter- tionoflow-thresholdmechanoreceptorsofthecontralat- nalmedullarylaminaonitsventralborder,thuswidening eral half of the body surface including the furry buccal to a sizeable area ventral to the ventral posterior medial pad (rat) or a bilateral representation of intraoral struc- nucleus (VPM). This part resembles the ventral poste- tures (cat) (Vahle-Hinz and Gottschaldt 1983). The car- rior inferior nucleus (VPI) of the monkey. Most of the toon in Fig. 1B shows the approximate proportions in neurons in the VPMp have somatic RFs and the major- the cat’s VP in a frontal plane, while in fact the complex ity are located on the head (Fig. 1d). The lateral part of extends caudomedially to rostrolaterally with the hind the VPp (VPLp) is a narrow band surrounding the ven- limbarearostraltothefaceinbothratandcat.Thesubnu- tral posterior lateral nucleus (VPL) ventrally, laterally cleiof theVPholding therepresentationsof thedifferent and dorsally. It merges with the lateral and medial parts parts of the body stand out from adjacent regions histo- of the PO and its RFs are located on the fore- and hind- logicallybydenserpackingandlargersomataofneurons limbs as well as on visceral organs (Fig. 1e). Thus with (Fig. 1a). Interspersed are smaller  GABAergic cells respect to somatic RFs, a coarse somatotopy is present with local axonal arbors (interneurons, about 25% of the running parallel to that of the VP proper. neurons) in the cat; these are virtually absent in the rat. While no nociceptive neurons are found inside the VP The projection neurons of the VP have large round so- of the cat, they may invade the laminae between subnu-

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Thalamic Nuclei Involved in Pain, Cat and Rat, Figure 1 Locations of nociceptive neurons in the lateral thalamus of the cat. (a, b) Subnuclei of the ventral posterior complex and adjacent regions as determined by histology (a), Nissl stain, coronal section, medial to the left, scale bar: 1 mm) and electrophysiological mapping of neuronal receptive fields (b). (c) Examples of neurons from the VPvp and the VP (camera lucida drawings from Golgi-stained tissue, scale bar: 50 μm). (d) Recording sites in VPp of nociceptive neurons with cutaneous receptive fields. Nociceptive-specific (dots) and multireceptive neurons (triangles). (e) Recording sites of visceroceptive neurons in VPp and PO determined by electrical stimulation of the pelvic nerve. Eml, external medullary lamina; POl, m, medial and lateral parts of the posterior complex; R, thalamic reticular nucleus; VMb, basal ventral medial nucleus (gustatory relay); VP, ventral posterior complex; VPp, periphery of VP; VPvp, ventral periphery of VP; VPMm, l, medial (intraoral RFs) and lateral (face RFs) parts of the ventral posterior medial nucleus; VPL, ventral posterior lateral nucleus (postcranial body RFs);ZI,zona incerta; scale bar: 1 mm. Modified from Vahle-Hinz et al. 1995 (b), Kniffki et al. 1993 (c), Kniffki and Vahle-Hinz 1987 (e), Brüggemann et al. 1994 (e). 2420 Thalamic Nuclei Involved in Pain, Human and Monkey clei of the VP as shown in Fig. 1b. In the rat, clustering of the rat to stimulation of uterus, vagina, colon, and skin. J Neu- of VP cells with similar RFs is even more pronounced rophysiol 69:557–568 2. Brüggemann J, Vahle-Hinz C, Kniffki K-D (1993) Representa- and thus laminae with nociceptive cells are more numer- tion of the urinary bladder in the lateral thalamus of the cat. J ously interspersed, contributing to the appearance of a Neurophysiol 70:482–491 mixed representation of mechanoreceptive and nocicep- 3. Brüggemann J, Vahle-Hinz C, Kniffki K-D (1994) Projections tive neurons described in the literature (for review see from the pelvic nerve to the periphery of the cat’s thalamic ven- tral posterolateral nucleus and adjacent regions of the posterior Willis 1997). Most of the somatic nociceptive neurons complex. J Neurophysiol 72:2237–2245 in the rat, however, are found in the PO. 4. Horn AC, Vahle-Hinz C, Petersen M et al. (1997) Projections from the renal nerve to the cat’s lateral somatosensory thalamus. Posterior Complex (PO) Brain Res 736:47–55 5. Horn AC, Vahle-HinzC, Brüggemann J et al. (1999) Responses of The somatosensory parts of PO adjoin VPL laterally neurons in the lateral thalamus of the cat to stimulation of urinary and dorsally and VPM dorsally (POm). The nuclear bladder, colon, esophagus, and skin. Brain Res 851:164–174 and subnuclear boundaries are not discernible histo- 6. Kniffki K-D, Vahle-Hinz C (1987) The periphery of the cat’s logically. PO receives inputs from the STT, the lateral ventroposteromedial nucleus (VPMp ): Nociceptive neurones. In: Besson J-M, Guilbaud G, Peschanski M (eds) Thalamus and Pain. cervical nucleus, the dorsal column, the nucleus of the Elsevier, Amsterdam, pp 245-257 solitary tract and the parabrachial area. These affer- 7. Kniffki K-D, Pawlak M, Vahle-Hinz C (1993) Scaling behavior ents carry nociceptive somatic and visceral signals. of the dendritic branches of thalamic neurons. Fractals 1:171–178 In the cat, the VPL and adjoining PO were found to 8. Vahle-Hinz C, Brüggemann J, Kniffki K-D (1995) Thalamic pro- p cessing of visceral pain. In: Bromm B, Desmedt J (eds) Pain and hold visceroceptive neurons with inputs from thoracic the Brain. From Nociception to Cognition. Advances in Pain Re- and pelvic visceral organs (Brüggemann et al. 1993; serach and Therapy, vol 22. Raven Press, New York, pp 125–141 Brüggemann et al. 1994; Horn et al. 1997; Horn et 9. Vahle-Hinz C, Detsch O (2002) What can in vivo electrophysi- ology in animal models tell us about mechanisms of anesthesia? al. 1999; Vahle-Hinz et al. 1995). Also in the rat, a Br J Anaesth 89:123–142 concentration of visceroceptive neurons in the region 10. Vahle-Hinz C, Freund I, Kniffki K-D (1987) Nociceptive neurons immediately surrounding the VP was found (Berkley et in the ventral periphery of the cat thalamic ventroposteromedial al. 1993). No viscerotopic organization is discernible nucleus. In: Schmidt RF, Schaible H-G, Vahle-Hinz C (eds) Fine Afferent Nerve Fibers and Pain. VCH Verlagsgesellschaft, Wein- but the response properties indicate that this region may heim, pp 440–450 be involved in the encoding, localization and referral 11. Vahle-Hinz C, Gottschaldt K-M (1983) Principal differences in of visceral pain. the organization of the thalamic face representation in rodents The somatic low-threshold RFs of PO neurons are of- and felids. In: Macchi G, Rustioni A, Spreafico R (eds) So- matosensory Integration in the Thalamus. Elsevier, Amsterdam, ten large and bilateral and include deep structures like pp 125–145 muscles and joints. In the rat, somatic nociceptive neu- 12. Vahle-Hinz C, Reeker W, Detsch O et al (2002) Antinociceptive rons with small RFs and stimulus encoding properties effects of anesthetics in vivo: Neuronal responses and cellular similar to those of the cat’s VP are found in the POm. mechanisms. In: Urban BW, Barann M (eds) Molecular and Ba- p sic Mechanisms of Anesthesia. Pabst Sci Publ, Lengerich, pp 516–524 Medial Thalamus 13. Willis WD (1997) Nociceptive functions of thalamic neurons. Nociceptive somatic and visceral neurons are found in In: Steriade M, Jones EG, McCormick DA (eds) Thalamus, Vol. a number of nuclei of the medial thalamus, including II, Experimental and Clinical Aspects. Elsevier, Amsterdam, pp 373–424 the central lateral and parafascicular nucleus of the in- tralaminarcomplex,themediodorsalnucleusandthenu- cleus submedius (for review see Willis 1997). The RFs are usually large, often bilateral, with convergent input Thalamic Nuclei Involved in Pain, Human from skin, muscles, jointsand viscera. There isno soma- and Monkey totopic or viscerotopic organization; thus these regions EDWARD JONES maynotbeinvolvedinthespatiallocalizationofapainful Center for Neuroscience, University of California, stimulus. In contrast, intensity is encoded in graded re- Davies, CA, USA sponses, a property important for the affective compo- [email protected] nent of pain. The nociceptive responses are particularly sensitive to the kind and depth of anesthesia. NS, WDR Synonyms andmultireceptiveneuronsoccurinthemediodorsaland intralaminar nuclei. The nucleus submedius receives a Nociceptive Coding in Lateral Thalamus; Lateral thala- dense projection from  lamina I of the spinal cord in mus encodes pain cats and nociceptive-specific somatic neurons here are more abundant than WDR neurons in both rats and cats. Description Based on anatomical considerations, afferent inputs, References cortical projections and electrophysiological evidence, 1. Berkley KJ, Guilbaud G, Benoist J-M, Gautron M (1993) Re- the core of the ventral posterior nuclei must be involved sponses of neurons in and near the thalamic ventrobasal complex in transmitting nociceptive information to the cortex. Thalamic Nuclei Involved in Pain, Human and Monkey 2421

Characteristics Single unit recordings both within and around the It is likely that many thalamic nuclei and therefore their perimeter of the ventral posterior nucleus of the tha- projection areas in the cerebral cortex are “involved” in lamus in monkeys and humans reveal the presence pain. However, despite many attempts to discredit it, it of neurons with both nociceptive-specific and  wide remains apparent that the ventral posterior nuclear com- dynamic range properties akin to those found in dorsal plex is that part of the thalamus that possesses the ap- horn neurons (e.g. Bushnell et al. 1993; Craig et al. propriateinputconnectionsandtherelevantcellular ma- 1994; Lee et al. 1999; Ohara and Lenz 2003; Willis chinery for relaying the qualitative features and periph- and Coggeshall 2004). Unfortunately, these have never erallocalizationofapainfulstimulus.Anecessarycorol- been satisfactorily identified as exclusively within the lary of thisisthat the cortical projection target of the ven- matrix, but it is clear that many of these recordings tral posterior complex, the post central gyrus, is a cen- have come not just from the matrix regions surround- tral element in the onward pathways to the perception ing VPM and VPL but also from within the heart of of pain. these nuclei themselves. From what we have described Theessay  SpinothalamicTerminations,CoreandMa- in the essay on spino- and spinal trigeminothalamic trix summarizes the newer connection tracing studies terminations mentioned above, it is unlikely (although that demonstrate not only the widespread terminations some have considered it controversial) that noci- or of the  central pain pathways in the primate thalamus thermo-specific neurons of spinal lamina I project only but also their relationships to cells within the heart of to neurons outside the confines of the ventral posterior theventralposteriornucleus,the  ventralposteriorme- nucleus, although their projections may be concentrated dial (VPM) and  ventral posterior lateral (VPL) nuclei. there in the matrix domain in monkeys and humans (and Here they appear to terminate preferentially on the ma- in comparable regions in cats). Of special note is the trix cells of the two nuclei, extending these terminations presence of neurons with nociceptive specific properties beyond the confines of  VPM and  VPL into and sur- within the heart of the ventral posterior nucleus. This rounding nuclei that are also characterized by the pres- carries the implication that these neurons project to ence of  calbindin-immunoreactive matrix cells. the primary somatosensory cortex and that has indeed

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Thalamic Nuclei Involved in Pain, Human and Monkey, Figure 1 Schematic view of the distribution of spinothalamic tract fibers in the thalamus of the macaque monkey and the cortical projections of the receiving nuclei. CL, central lateral nucleus; Po, posterior nucleus; Pla, anterior pulvinar nucleus; SG-L, limitans-suprageniculate nucleus; VLp, posterior ventral lateral nucleus; VMb, basal ventral medial nucleus; VPI, ventral posterior inferior nucleus; VPL, ventral posterior lateral nucleus; VPM, ventral posterior medial nucleus; ZI, zona incerta. 2422 Thalamic Nuclei Involved in Pain, Human and Monkey been directly demonstrated in a small number of cases Oharaetal.2004a,2004b).Theseimagingresults,more- (Kenshalo et al. 1980). over, tend to be supported by the results of single unit The presence of neurons with properties appropriate for studies in monkeys (Robinson and Burton 1980; Ken- relaying the details of the modality, location and inten- shalo et al. 2000). The role of the lateral areas has been sity of a painful stimulus within the heart of the thalamic adduced mainly from lesion studiesin humans, butthese nucleus that projects to the primary somatosensory cor- have been variously interpreted. tex should not be taken to imply that these neurons are My own view is that lesions involving the parietal op- found only therein. They are indeed found within all or erculum (which might mean involvement of the second most of the other sites of termination of the spinothala- somatosensory area alone but could equally undercut mic tracts as a whole and within those sites outside the fibers approaching the postcentral gyrus) seem to alter ventral posterior nucleus to which neurons specifically the sensory-discriminative aspects of pain apprecia- located in the superficial dorsal horn project (reviewed tion, while those affecting regions located in insular in Willis et al. 2002). The cortical targets of these other and postinsular regions tend to alter affective and moti- parts of the thalamus, which include the  ventral pos- vational aspects and can result in pain asymbolia (see, terior inferior and  basal ventral medial nuclei of the for example, Greenspan et al. 1999; Ostrowsky et al. ventral posterior complex, the adjacent matrix-filled do- 2002). This still leaves out, however, the prefrontal and mains of the  posterior nucleus and  anterior pulv- cingulate areas. Perhaps it is their activation in pain inar nucleus and the caudal intralaminar nuclei, are di- states that represents the inputs from thalamic nuclei verse and include the second somatosensory area, other such as the caudal intralaminar? peri-insular areas and parts of the prefrontal and pos- sibly anterior cingulate cortex. The broad implication is the classical one that the multi-dimensional charac- References ter of that sensation that we call pain is reflected in in- 1. Bushnell MC, Duncan DH, Tremblay N (1993) Thalamic VPM puts to regions of cortex whose known or conjectured nucleus in the behaving monkey. I. Multimodal and discrim- inative properties of thermosensitive neurons. J Neurophysiol functionalconnotationsare appropriate foreach of these 69:739–752 dimensions. But there is still no reason to rule out the be- 2. Coghill RC, Talbot JD, Evans AC et al. (1994) Distributed pro- lief thatthe primary somatosensory cortexisthe primary cessing of pain and vibration by the human brain. J Neurosci route to the centers for perception of the quality, loca- 14:4095–4108 3. Craig AD, Bushnell MC, Zhang E-T et al. (1994) A thalamic tion and intensity of a painful stimulus. This is not the nucleus specific for pain and temperature sensation. Nature place to consider all the data that imply the dissociation 372:770–773 of the sensory discriminative and affective-motivational 4. Davis KD, Kwan CL, Crawley AP et al. (1998) Functional MRI dimensions of pain in relation to different cortical areas study of thalamic and cortical activations evoked by cutaneous heat, cold, and tactile stimuli. J Neurophysiol 80:1533–1546 but there is a growing literature (often misinterpreted or 5. Gelnar PA, Krauss BR, Sheehe PR et al. (1999) A comparative misrepresented) in this field that is covered in other es- fMRI study of cortical representations for thermal painful, vibro- says in this encyclopedia. tactile, and motor performance tasks. Neuroimage 10:460–482 Functional imaging studies in humans support the view 6. Greenspan JD, Lee RR, Lenz FA (1999) Pain sensitivity alter- ations as a function of lesion location in the parasylvian cortex. of widespread thalamocortical projections in the central Pain 81:273–282 pain system. Most of the areas referred to in the preced- 7. Kenshalo DR Jr, Giesler GJ Jr, Leonard RB et al. (1980) Re- ing paragraph show functional activation in response to sponses of neurons in primate ventral posterior lateral nucleus application of painful stimuli to the skin or stimuli en- to noxious stimuli. J Neurophysiol 43:1594–1614 8. Kenshalo DR, Iwata K, Sholas M, Thomas DA (2000) Re- gendered in deeper tissues. Areas of the cortex report- sponse properties and organization of noiceptive neurons in edly activated during the appreciation of a painful stim- area 1 of monkey primary somatosensory cortex. J Neurophysiol ulus include the first and second somatosensory areas, 84:719–729 9. Lee J-I, Dougherty PM, Antezana D et al (1999) Responses of the insula and the anterior cingulate gyrus (e.g. Coghill neurons in the region of human thalamic principal somatic sen- et al. 1994; Davis et al. 1998; Gelnar et al. 1999). Trying sory nucleus to mechanical and thermal stimuli graded into the to correlate these observations with electrophysiologi- painful range. J Comp Neurol 410:541–555 cal reports from monkeys and the effects of stimulation 10. Ohara S, Lenz FA (2003) Medial lateral extent of thermal and pain sensations evoked by microstimulation in somatic sensory or lesions in humans presents a confusing picture from nuclei of human thalamus. J Neurophysiol 90:2367–2377 which workers committed to any point of view about the 11. Ohara S, Crone NE, Weiss N et al. (2004a) Cutaneous painful cortical representation of pain, however eccentric, can laser stimuli evoke responses recorded directly from pri- derive sustenance. mary somatosensory cortex in awake humans. J Neurophysiol 91:2734–2746 When we look at the results of recording or imaging of 12. Ohara S, Crone NE, Weiss N et al. (2004b) Attention to pain thepostcentralgyrusafterpresentationofpainfulstimuli is processed at multiple cortical sites in man. Exp Brain Res to human subjects, it is difficult to escape the conclusion 156:513–517 that the primary somatosensory cortex is at the heart of 13. Ostrowsky K, Magnin M, Ryvlin P et al. (2002) Representation of pain and somatic sensation in the human insula: a study of the territory involved in nociception but more lateral ar- responses to direct electrical cortical stimulation. Cereb Cortex eas are likely to be involved as well (Treede et al. 2000; 12:376–385 Thalamic Plasticity and Chronic Pain 2423

14. Robinson CJ, Burton H (1980) Somatic submodality distribution findings regarding plasticity in processing of tactile in- within the second somatosensory (SII), 7b, retroinsular, postau- formation. ditory and granular insular cortical areas of M. fascicularis.J Comp Neurol 192:93–108 In contrast to the hundreds of papers that have described 15. Treede RD, Apkarian AV, Bromm B et al. (2000) Cortical repre- reorganization of the primary somatosensory cortex af- sentation of pain: functional characterization of nociceptive areas ter deafferentation, relatively few have studied changes near the lateral sulcus. Pain 87:113–119 at the thalamic level. However, the variables that affect 16. Willis WD Jr, Coggeshall RE (2004) Sensory Mechanisms of the Spinal Cord, 3rd edn. Plenum, New York thalamic and cortical reorganization are the same: the 17. Willis WD Jr, Zhang X, Honda CN et al. (2002) A critical review age of the animal at the time of the damage; the extent of the role of the proposed VMpo nucleus in pain. J Pain 3:79–94 and location of the damage; and the time thathas expired since the damage. Neonatal damage, or even trimming of whiskers from birth to decrease sensory experience, can produce dramatic changes in the somatotopic map Thalamic Pain within the rodent thalamus (e.g. Nicolelis et al. 1997; Simons and Land 1994). These developmental changes  are reflected in morphological changes in the structural Central Pain, Diagnosis representation of whiskers in the rodent thalamus, the “ barreloids”. In particular, the separation between af- fected barreloids is lost, suggesting a profound interfer- ence with the migration ofthalamic neurons. The critical Thalamic Physiology Changes Occurring period for the thalamus is intermediate between the ear- in Patients with Chronic Pain lier developing brainstem and the later developing cor- tex. In the adult animal, immediate reorganization of the  Thalamus,ReceptiveFields,ProjectedFields,Human  ventral posterior lateral nucleus (VPL) thalamus, by reversibly blocking afferent inputs from the skin follow- ing local anesthetic injections, has been demonstrated in several species including man (Nicolelis et al. 1993; Thalamic Plasticity and Chronic Pain see Dostrovsky 1999 for other references). This results 1 in the appearance of new and/or enlargement of the RFs JONATHAN O. DOSTROVSKY , 2 of individual neurons. Of particular interest is a study DOUGLAS RASMUSSON 1Department of Physiology, University of Toronto, that found that this unmasking was greatly reduced if the somatosensory cortex was inactivated at the time of Toronto, ON, Canada  2Department of Physiology and Biophysics, Dalhousie peripheral deafferentation, suggesting that Cortical University, Halifax, NS, Canada Feedback plays an important role in these immediate [email protected] changes (Krupa et al. 1999). Longer-term plasticity of the thalamus (requiring sev- eral months) has been demonstrated after a variety of T Synonyms different types of peripheral nerve damage. These in- Functional Changes in Thalamus; Chronic Pain, Thala- clude transection of median and ulnar nerves in squirrel mic Plasticity monkeys (Garraghty and Kaas 1991), digit amputation in raccoons (Rasmusson 1996), dorsal rhizotomies in Definition primates(JonesandPons1998),aswellascentrallesions affecting the ascending branch of peripheral afferents in Long term changes in processing of somatosensory in-  thedorsalcolumns(PollinandAlbe-Fessard1979).Tha- puts in thalamus as a result of deafferentation and/or lamic reorganization also results from destruction of the chronic pain. dorsal column nuclei, which provide the major, direct input to VPL and to the spinothalamic tract. Lesioning Characteristics the gracile nucleus in rats results in expansion of upper Most of the information regarding  plasticity in the so- limb and shoulder representations (Parker et al. 1998; matosensory system at supraspinal levels concerns the Wall and Egger 1971). In all these cases, the major effect processing and representation of non-nociceptive tactile is an expansion of intact adjacently represented regions inputs.Thisismainlybecauseitisdifficulttodeterminea into the region that has been deafferented. In addition, clearmapofthebodyrepresentationofneuronsrespond- spinothalamic tract lesions in sub-human primates have ing to nociceptive inputs. However, it is likely that there been shown to increase the spontaneous firing rate and are at least some common mechanisms between plastic- responses to mechanical stimulation of the skin, and in- ity of innocuous information and nociceptive informa- crease the degree of  bursting activity in low threshold tion processing, and thus the first section will deal with slowly adapting neurons (Weng et al. 2003). 2424 Thalamic Projections

Recordings and stimulation in human thalamus of normally elicit only non-painful parasthesia (see refer- chronic pain patients suffering spinal cord damage ences in Dostrovsky 1999; Weng et al. 2003). or amputation reveal an expansion of the intact re-  Thalamus, Dynamics of Nociception gions into deafferented regions, and the existence of neurons firing spontaneously in bursts. Stimulation in References such regions usually evokes sensations referred to the 1. Dostrovsky JO (1999) Immediate and Long-Term Plasticity in deafferented region or phantom limb. Some of these Human Somatosensory Thalamus and its Involvement in Phan- alterations may also be involved in mediating the pa- tom Limbs. Pain 6:37–43 2. Dostrovsky JO, Guilbaud G (1990) Nociceptive Responses tients’ pain (see references in Dostrovsky 1999; Weng in Medial Thalamus of the Normal and Arthritic Rat. Pain et al. 2003). 40:93–104 Few studies have examined the mechanisms responsible 3. Garraghty P, Kaas J (1991) Functional Reorganization in Adult for thalamic plasticity. Electron microscopic evidence Monkey Thalamus after Peripheral Nerve Injury. NeuroReport 2:747–750 for synaptogenesis, presumably resulting from sprout- 4. Jones EG, Pons TP (1998) Thalamic and Brainstem Contribu- ing of surviving axons, has been found in the rat after tions to Large-Scale Plasticity of Primate Somatosensory Cortex. dorsal column nuclei lesions (Wells and Tripp 1987). Of Science 282:1121–1125 potential interest is the decrease in  GABAA receptors 5. Krupa DJ, Ghazanfar AA, Nicolelis MA (1999) Immediate Tha- lamic Sensory Plasticity Depends on Corticothalamic Feedback.  that follows dorsal rhizotomy in primates (Rausell Proc Natl Acad Sci USA 96:8200–8205 et al. 1992). In addition, other studies have revealed 6. Nicolelis MA, Lin RCS, Chapin JK (1997) Neonatal Whisker changes in the morphology of  GABA terminals fol- Removal Reduces the Discrimination of Tactile Stimuli by Tha- lamic Ensembles in Adult Rats. J Neurophysiol 78:1691–1706 lowing dorsal column lesions. Decreased inhibitory 7. Nicolelis MAL, Lin RCS, Woodward DJ et al. (1993) Induction control could contribute directly or indirectly to the of Immediate Spatiotemporal Changes in Thalamic Networks by plasticity mechanisms responsible for thalamic reorga- Peripheral Block of Ascending Cutaneous Information. Nature nization, and may also result in increased RF sizes and 361:533–536 8. Parker JL, Wood ML, Dostrovsky JO (1998) A Focal Zone of lowered thresholds of nociceptive neurons in thalamus Thalamic Plasticity. J Neurosci 18:548–558 (see references in Weng et al. 2003). There is also elec- 9. Pollin L, Albe-Fessard D (1979) Organization of Somatic Tha- trophysiological evidence that many cells in VPL have lamus in Monkeys with and without Section of Dorsal Spinal  subliminal receptive fields, and these may provide Tracts. Brain Res 173:431–449  10. Rasmusson DD (1996) Changes in the Organization of the Ven- an important substrate for the expansion of receptive troposterior Lateral Thalamic Nucleus after Digit Removal in fields following deafferentation (Dostrovsky 1999). Adult Raccoon. J Comp Neurol 364:92–103 There have been several studies in animals showing 11. Rausell E, Cusick CG, Taub E et al. (1992) Chronic Deaf- greatly increased responses, receptive field sizes, and ferentation in Monkeys Differentially Affects Nociceptive and Nonnociceptive Pathways Distinguished by Specific Calcium- decreased thresholds of nociceptive neurons in me- Binding Proteins and Down-Regulates γ-Aminobutyric Acid dial and lateral (VPL) thalamus following peripheral Type A Receptors at Thalamic Levels. Proc Natl Acad Sci USA damage, inflammation, or central damage. Although 89:2571–2575 it is likely that some of these alterations were due to 12. Simons DJ, Land PW (1994) Neonatal Whisker Trimming Pro- duces Greater Effects in Nondeprived than Deprived Thalamic changes at the thalamic level, it is difficult to assess Barreloids. J Neurophysiol 72:1434–1447 to what extent these were due to neuroplastic changes 13. Wall PD, Egger MD (1971) Formation of New Connexions occurring at spinal and trigeminal levels (e.g. Dostro- in Adult Rat Brains after Partial Deafferentation. Nature 232:542–545 vsky and Gulibaud 1990; see references in Weng et al. 14. Wells J, Tripp LN (1987) Time Course of Reactive Synaptoge- 2003). nesis in the Subcortical Somatosensory System. J Comp Neurol Severalstudieshavereportedthatfollowingdeafferenta- 255:466–475 tion and  CNS damage leading to chronic pain, there is 15. Weng HR, Lenz FA, Vierck C et al. (2003) Physiological Changes in Primate Somatosensory Thalamus Induced by Deafferentation an increase in bursting activity of neuronsin and near the are Dependent on the Spinal Funiculi that are Sectioned and Time deafferented region in human thalamus, and have sug- following Injury. Neuroscience 116:1149–1160 gested that this may be related to the development of central pain. Bursting cells have also been observed in chronic pain patients (see  Thalamic Bursting Activity and references in Weng et al. 2003). Thalamic Projections Of considerable interest are observations in humans on the incidence of stimulation-evoked pain. In non-pain  Corticothalamic and Thalamocortical Interactions patients the incidence of evoking pain by stimulation within  ventral basal nucleus (VB) is very low. How- ever, in some types of pain patients, and in particular in  post-stroke central pain patients, the incidence is Thalamic Reorganization much higher, suggesting that neuroplastic changes have occurredinthethalamocorticalsysteminthesecasesthat are causing pain to be perceived by thalamic stimuli that  Thalamus, Dynamics of Nociception Thalamo-Amygdala Interactions and Pain 2425

human neurosurgicaldata, he noted that ablation of sev- Thalamic Response to Experimental Pain eral limbic forebrain sites proved effective in reducing in Humans the ‘agonizing’ pain associated with advanced cancer. These areasinclude the anterior cingulate cortex (ACC),  Human Thalamic Response to Experimental Pain medial thalamic nuclei (centromedian and parafascic- (Neuroimaging) ular nuclei), amygdala, and prefrontal cortex. Damage of these structures produced no loss of the  sensory- discriminative dimension of pain, but was efficacious in alleviating its affective-motivational dimension. Sweet Thalamic Reticular Nucleus pointed out that the mechanisms responsible for this dis- sociative analgesia were poorly understood, and called Synonyms for the development of animal models and systematic TRN research programs that could provide insights into the neurobiology of the affective dimension of pain. Definition Subsequent research provided convergent evidence in support of the involvement of the limbic-forebrain A nucleus that surrounds the thalamus. It receives inputs in processing the affective-motivational dimension of fromthecortexandthalamusandprojectsbacktothetha- human pain. Additional human neurosurgical obser- lamus with inhibitory connections. Neurones in this tha- vations confirmed the involvement of the  medial lamic nucleus are inhibitory GABAergic neurones that thalamus and ACC in pain perception. Ablations of provide inhibition onto thalamic relay neurones. TRN these areas remain an effective treatment in alleviat- neurones do not project to the cerebral cortex. ing chronic intractable pain (Hassenbusch et al. 1990;  Thalamocortical Loops and Information Processing  Whittle and Jenkinson 1995). The chronic pain state Thalamus, Metabotropic Glutamate Receptors appears to be mediated by sustained abnormal neural  Thalamus, Nociceptive Neurotransmission activity within the limbic forebrain. High frequency spontaneous neural activity was recorded from medial thalamic nuclei in patients with deafferentation pain Thalamo-Amygdala Interactions and Pain (Rinaldi et al. 1991). High frequency stimulation of the medial thalamus produced reports of intense pain 1 2 GEORGE S. BORSZCZ ,S.E.HARTE in human subjects, which was suppressed by treatment 1Department of Psychology, Wayne State University, with the μ-opiate agonist fentanyl (Velasco et al. 1998). Detroit, MI, USA Neuroimaging studies of the human pain, experimental 2Department of Internal Medicine, Chronic Pain and and clinical, also revealed a limbic-forebrain matrix that Fatigue Research Center, Rheumatology University of underlies the processing of the affective-motivational Michigan Health System, Ann Arbor, MI, USA dimension of pain (see review Derbyshire 2000). These [email protected], [email protected] studies consistently report activation of the amygdala, ACC, insula, prefrontal cortex, and medial thalamus. T Synonyms Following the  parallel pain processing model of Melzack and Casey (1968), the results of these neuro- Affective analgesia; affective pain processing; Limbic surgicaland neuroimaging studieshavebeeninterpreted Forebrain Matrix; pain asymbolia as reflecting the processing of noxious stimulation by  Definition the ‘ medial pain system’ (Vogt and Sikes 2000). The medial pain system is proposed to process nox- Processing the  affective-motivational dimension of ious stimulation transmitted by medially projecting pain experience. Suppression of nociceptive transmis- spinothalamic pathways (i.e. spinoreticulothalamic sion through this limbic forebrain matrix produces tract). This projection system terminates in medial tha- selective inhibition of the affective reaction to pain lamic nuclei that project to limbic forebrain structures (affective analgesia). Interactions between limbic fore- that underlie processing of the affective-motivational brain sites and the midbrain periaqueductal gray is one dimension of pain. The ACC, insula, and prefrontalcor- mechanism through which morphine acts to produce tex are principal forebrain targets of medial thalamic affective analgesia. projections (Vogt and Sikes 2000). The medial thala- mus also projects to the amygdala that is reciprocally Characteristics interconnected with the medial thalamus, ACC, and W.H. Sweet (1980), the eminent neurosurgeon and pain insula. The amygdala and medial thalamus also receive researcher,observedthecriticalneedtoevaluatetheneu- nociceptive afferents from the spinal dorsal horn, re- ral mechanisms that generate and suppress the affective- layed via the parabrachial nucleus (Bernard and Besson motivational dimension of pain. In reviewing the extant 1990; Bourgeais et al. 2001). The processing of noxious 2426 Thalamocortical and Corticothalamic Interactions stimulation by this limbic-forebrain matrix generates action of vPAG-administered morphine (Ma and Han the emotional reaction to pain, coordinates relevant 1991). motor activity, and supports the development of fear conditioning and avoidance responding (Derbyshire References 2000). 1. Bernard JF, Besson JM (1990) The Spino(trigemino)pontoamyg- Alternately, the ‘ lateral pain system’ processes nox- daloid Pathway: Electrophysiological Evidence for an Involve- ious stimulation transmitted by laterally projecting ment in Pain Processes. J Neurophysiol 63:473–490 2. Borszcz GS (1999) Differential Contributions of Medullary, Tha- spinothalamic and trigeminothalamic pathways that lamic, and Amygdaloid Serotonin to the Antinociceptive Ac- terminate in lateral thalamic nuclei (i.e. VPL and tion of Morphine Administered into the Periaqueductal Gray: A VPM). Projections of the lateral thalamic nuclei to Model of Morphine Analgesia. Behav Neurosci 113:612–631 the primary and secondary somatosensory cortices are 3. Borszcz GS, Johnson CP,Fahey KA (1994) Comparison of Motor Reflex and Vocalization Thresholds following Systemically Ad- proposed to underlie the processing of the sensory- ministered Morphine, Fentanyl, and Diazepam in the Rat: Assess- discriminative dimension of the pain experience. This ment of Sensory and Performance Variables. Pharmacol Biochem dimension of pain signals the location, intensity, and Behav 49:827–834 physical properties of a noxious stimulus. 4. Borszcz GS, Streltsov NG (2000) Amygdaloid-Thalamic In- teractions Mediate the Antinociceptive Action of Morphine Systemic administration of morphine preferentially Microinjected into the Periaqueductal Gray. Behav Neurosci suppresses the affective reaction of humans and ani- 114:574–584 mals to noxious stimulation (Borszcz et al. 1994; Price 5. Bourgeais L, Monconduit L, Villanueva L et al. (2001) et al. 1985). This effect is mediated by the inhibition of Parabrachial Internal Lateral Neurons Convey Nociceptive Messages from the Deep Laminas of the Dorsal Horn to the pain transmission through limbic forebrain structures Intralaminar Thalamus. J Neurosci 21:2159–2165 that process the affective dimension of pain (Casey et 6. Casey KL, Svensson P, Morrow TJ, Raz J, Jone C, Minoshima S al. 2000). The ventrolateral division of the midbrain pe- (2000) Selective Opiate Modulation of Nociceptive Processing in the Human Brain. J Neurophysiol 84:525–533 riaqueductal gray (vPAG) is a major site through which 7. Derbyshire SWG (2000) Exploring the Pain ‘Neuromatrix’. Curr morphine acts to suppress pain transmission. Through Rev Pain 4:467–477 its descending projections to the rostral ventromedial 8. Hassenbusch SJ, Pillay PK, Barnett GH (1990) Radiofre- medulla, thevPAGinhibitspain transmission atthelevel quency Cingulotomy for Intractable Cancer Pain using Stereo- taxis Guided by Magnetic Resonance Imaging. Neurosurgery of the spinal dorsal horn. The vPAG also contributes 27:220–223 ascending projections that suppress pain transmission 9. Ma QP,Han JS (1991) Neurochemical Studies on the Mesolimbic directly within the limbic forebrain (Borszcz 1999). Circuitry of Antinociception. Brain Res 566:95–102 The vPAG and adjacent dorsal raphé nucleus provide 10. Munn EM, Borszcz GS (2002) Increases in the Release and Metabolism of Serotonin in Nucleus Parafascicularis Thalami ascending serotonergic projections to the medial tha- following Systemically Administered Morphine in the Rat. lamus (parafascicular nucleus) and amygdala, and the Neurosci Lett 332:151–154 microinjection of morphine into the vPAG increases 11. Price DD, Von der Gruen A, Miller J et al. (1985) A Psychophys- the release and metabolism of serotonin in these sites ical Analysis of Morphine Analgesia. Pain 22:261–269 12. Rinaldi PC, Young RF, Albe-Fessard D et al. (1991) Spontaneous (Munn and Borszcz 2002; Tao and Auerbach 1995). Neuronal Hyperactivity in the Medial and Intralaminar Thala- Moreover, the suppression of rats’ affective reaction to mic Nuclei of Patients with Deafferentation Pain. J Neurosurg noxious stimulation following injection of morphine 74:415–421 13. Sweet WH (1980) Mechanisms of Chronic Pain (Neuralgias and into vPAG is reversed by bilateral administration of Certain Other Neurogenic Pain). In: Bonica JJ (ed)Pain. Raven serotonin antagonists into either the parafascicular Press, New York, pp 287–303 nucleus or amygdala (Borszcz 1999). 14. Tao R, Auerbach SB (1995) Involvement of the Dorsal Raphe The parafascicular nucleus and amygdala appear to but not Median Raphe Nucleus in Morphine-Induced Increases in Serotonin Release in the Rat Forebrain. Neuroscience interact in the production of affective analgesia fol- 68:553–561 lowing the injection of morphine into the vPAG. The 15. Velasco M, Brito F, Jimenez F et al. (1998) Effect of Fentanyl and unilateral administration of serotonin antagonists into Naloxone on a Thalamic Induced Painful Response in Intractable the parafascicular nucleus or amygdala failed to alter Epileptic Patients. Stereotact Funct Neurosurg 71:90–102 16. Vogt BA, Sikes RW (2000) The Medial Pain System, Cingulate the antinociceptive action of vPAG-administered mor- Cortex, and Parallel Processing of Nociceptive Information. Prog phine. However, the combined unilateral administration in Brain Res 122:223–235 of serotonin antagonists into the parafascicular nucleus 17. Whittle IR, Jenkinson JL (1995) CT-Guided Stereotactic Antero- and amygdala was as effective as their bilateral admin- Medial Pulvinotomy and Centromedian-Parafascicular Thalam- otomy for Intractable Malignant Pain. Br J Neurosurg 9:195–200 istration into either site in reversing the antinociceptive action of morphine injected into the vPAG (Borszcz and Streltsov 2000). These findings suggest that a func- tional interaction exists between the medial thalamus, Thalamocortical and Corticothalamic amygdala, and vPAG in mediating affective analgesia. Evidence also exists for the interaction between the Interactions vPAG and other limbic forebrain sites (nucleus ac- cumbens, habenula) in mediating the antinociceptive  Corticothalamic and Thalamocortical Interactions Thalamocortical Loops and Information Processing 2427

Characteristics Thalamocortical Dysrhythmia To understand how information is processed in a tha- lamocortical system, it is important to identify and fol- Synonyms low the route of information transfer. A recent sugges- TCD tion based on thalamic circuitry is that not all pathways are equivalent, but instead can be divided into “drivers” Definition which are the information bearing pathways and “mod- ulators” which serve to modulate theflowofinformation A pathophysiological chain reaction at the origin of rather than transmitting it. How thismight apply tocorti- neurogenic pain. It consists of: 1) a reduction of ex- cal processing in general and cortical processing of pain citatory inputs onto thalamic cells, which results in more specifically is best explained by considering how cell membrane hyperpolarization, 2) the production this idea has led to important changes in our thinking of of low-threshold calcium spike bursts by deinactiva- thalamic circuitry. tion of calcium T-channels, discharging at low (theta) frequency, 3) a progressive increase of the number of thalamocortical modules discharging at theta fre- Drivers and Modulators quency, and 4) a cortical high frequency activation Figure 1 shows the basic circuit of the thalamus, which through asymmetric corticocortical inhibition. These varies only slightly among thalamic relays. As argued events have been documented by thalamic and cortical previously, the inputs to relay cells can be divided into recordings in patients suffering from peripheral and two basic types, “drivers” and “modulators” and these central neurogenic pain. differ on a number of different morphologicaland func-  Thalamotomy for Human Pain Relief tionalgroundsthatarebrieflysummarizedinTable1(for  Thalamus, Dynamics of Nociception details, see Sherman and Guillery 2001, 2002; Guillery and Sherman 2002a). The first pair of listed differences arepropertieslimitedtothalamus,buttheremainderrep- resent criteria that can be applied anywhere in the cen- Thalamocortical Fibers tral nervous system. The drivers are the input that brings the information to be relayed. Examples are retinal input to the lateral geniculate nucleus, medial lemniscal input Definition to the  ventral posterior nucleus and, as noted below Axons with cell bodies located in the thalamus and ter- for some thalamic relays, layer 5 input from cortex. The minations in the cortex. modulatorsareeverythingelseandtheirmainfunctionis  Corticothalamic and Thalamocortical Interactions to control the level and type of information relayed from drivers through thalamus to cortex. Examples are the lo- cal  GABAergiccells(i.e.,interneuronsandcellsofthe thalamic reticular nucleus), feedback fromcorticallayer Thalamocortical Loops and Information 6 and a projection from the brainstem reticular forma- T Processing tion. Drivers represent relatively few of the synaptic in- putstorelaycells(onlyabout5–10%),buttheirsynapses S. MURRAY SHERMAN are relatively powerful. The other 90–95% of synapses Department of Neurobiology, State University of New onto relay cellsare divided roughlyequally among mod- York, Stony Brook, NY, USA ulatory inputs from local GABAergic cells, from corti- [email protected] cal layer 6 and from the brainstem. The modulators re- quirethevastmajorityofinputsformanysubtlerolesthat Synonyms affect the relay of driver inputs (Sherman and Guillery 2001, 2002; Guillery and Sherman 2002a). Cortical Information Flow; Corticortical Pathways The main difference between thalamic relays is the ori- gin of the driver input; the modulators are basically sim- Definition ilar throughout thalamus, although there is some varia- Until recently, communication among related corti- tion (Jones 1985; Sherman and Guillery 2001). cal areas (e.g., those for somatosensation and pain) The understanding that inputs to relay cells can be di- was thought to involve direct connections. We (Sher- vided into drivers and modulators and that the former man and Guillery 2001; Sherman and Guillery 2002; largely define the function of a thalamic relay has im- Guillery and Sherman 2002a; Guillery and Sherman plications that may extend beyond thalamus (see also 2002b) suggest a radically new view in which many and below). Thus the  lateral geniculate nucleus is largely perhaps all corticocortical communications involve a definedasarelayofretinalinformation.Itisimportantto cortico-thalamo-cortical route. understandthatconsiderationofanatomicalinformation 2428 Thalamocortical Loops and Information Processing

Thalamocortical Loops and Information Processing, Figure 1 Schema of inputs to thalamic relay cells. Abbreviations: 5-HT, serotonin; ACh, acetyl- choline; BRF, brainstem reticular formation; GABA, gamma-aminobutyric acid; Glu, glutamate; LGN, lateral geniculate nucleus; NA, noradrenalin; TRN, thalamic reticular nucleus. alone can obscure this. For the lateral geniculate nucleus However,therecentrealizationthatdriversformanytha- for instance, only 5-10% of synapses onto relay cells de- lamicrelaysoriginateinlayer5ofcortexledtoadivision rive from retina and roughly one third derive from brain- of thalamus into “first order” and “higher order” relays, stem. If we had only these anatomical data, most of us and this is summarized in Fig. 2 (Sherman and Guillery would conclude that the lateral geniculate nucleus re- 2001, 2002; Guillery and Sherman 2002a). First order layed brainstem information and that retinal input pro- relays transmit to cortex a particular type of informa- vided some obscure, minor function. In other words, we tion (e.g. retinal) for the first time, whereas higher or- would badly misconstrue this thalamic relay. der relays are involved in further transmission of such information between cortical areas. The higher order re- lay can be between a first order and higher order cortical First and Higher Order Relays area (as shown in Fig. 2) or between two higher order Thus identifying the driver is a major key in determining corticalareas(notshown).Higherorderrelayshavebeen the role played by a thalamic relay. For instance, we de- identified for the major sensory systems, the pulvinar for fine the role of the  lateral geniculate nucleus based on vision,theposteriormedialnucleusforsomatosensation its relay of retinal axons and that of the ventral posterior (and thus for pain) and the magnocellular division of the nucleus based on its relay of  medial lemniscus axons. medial geniculate nucleus for hearing. Other examples However, until recently, the role played by many thala- ofhigherorderrelayshavealsobeenidentified(seeSher- mic relays remained a mystery, because it was not clear man and Guillery 2001, 2002). what was being relayed. We used to think that the role Several features from Fig. 2 bear further emphasis. All of the thalamus was to relay subcortical information to thalamic relays receive a modulatory input from layer cortex and for large regions of thalamus, such as much 6 of cortex that is mainly feedback, whereas only the of the pulvinar, it was not clear what was the subcortical higher order relays receive in addition a layer 5 cortical source being relayed. input and this is feedforward. Note also that the driver Thalamocortical Loops and Information Processing 2429

Thalamocortical Loops and Information Processing, Figure 2 First order (FO; left) and higher order (HO; right) thalamic relays. For simplicity, connections to relay cells from interneurons and brainstem are omitted. “Glomerulus” refers to a complex synaptic zone that is ubiquitous to thalamus and that is often associated with driver input.

T

Thalamocortical Loops and Information Processing, Figure 3 Involvement of higher order thalamic relays in corticocortical communication. For simplicity inputs from interneurons and cells of the thalamic reticular nucleus omitted. Abbreviations as in Fig. 1 plus: MGNv, ventral region of medial geniculate nucleus; MGNmagno; magnocellular region of medial geniculate nucleus; POm, posterior medial nucleus; VP, ventral posterior nucleus. afferents, both subcortical to first order relays and from ferents to the lateral geniculate nucleus branch to also layer 5 for higher order relays, are branchesofaxonsthat innervate midbrain structures associated with control of also innervate an extrathalamic target, which tends to be pupil size, eye movements, etc and many layer 5 affer- “motor” in nature; this is true for many and perhaps all ents to higher order thalamic relays also innervate many driverinputs(fordetails,seeGuilleryandSherman2002 levels of the brainstem and may extend input to spinal a, b; Guillery 2003). For instance, many or all retinal af- levels.Itisasiftheinformationrelayedtocortexthrough 2430 Thalamocortical Loops and Information Processing thalamusisacorollaryofmotorcommandsanditisthese thalamicrelay.Suchbenefitsarebeyondthescopeofthis motor commands that serve as the basis of perceptual in- essay to cover, but the reader can learn more of this from formation acted upon and further elaborated by cortex other sources (Sherman and Guillery 2001; Guillery and (Guillery and Sherman 2002 a, b; Guillery 2003). Sherman 2002a). It is also worth noting that, as sufficient information re- To place this scheme in the proper perspective, it is im- garding various thalamic relays develops regarding the portant to appreciate that most prevailing conceptions division into first order and higher order, the large ma- about functioning of cortical areas are based on direct jority of thalamus seems to be devoted to higher order connections between areas. For instance, the best stud- relays. ied is visual cortex, which is divided into more than 30 discreteareasinhumansandthedetailedschemeoffunc- Role of Thalamus in Corticocortical Communication tional organization is based almost entirely on the pat- Figure 3 summarizes the major implication of this divi- tern of direct corticocortical connections, with no place sion of thalamic relays into first order and higher order for thalamus (Van Essen et al. 1992; Kandel et al. 2000). for cortical functioning. Information of a particular sort A similar view dominates thinking about the organiza- first reaches cortex via a first order relay; this can apply tion of somatosensory cortical areas responsible for the to primary information about vision, sounds, pain, etc. cortical processing of pain. Understanding how cortical Further cortical processing of this primary information areas process information requires first identifying the isbasedoncortico-thalamo-corticalpathwaysinvolving routes of information and, if the driver/modulator dis- higher order thalamic relays. This view of corticocorti- tinction holds for cortical pathways as it seems to in tha- cal processing has the interesting feature that any new lamus, it then becomes essential to distinguish among information reaching a cortical area, whether initiated the direct corticocortical pathways those that are drivers subcortically or in another cortical area, benefits from a from those that are modulators. As it happens, the cur-

Thalamocortical Loops and Information Processing, Figure 4 Conventional (upper) versus alternate (lower) views of cortical processing. Thalamocortical Neurones 2431 rent views of cortical organization consider only direct lamic relays involved in pain processing could be key. corticocortical connections that have been identified al- The best candidate for the higher order thalamic relay mostentirelywithanatomicaltechniquesandanimplied of pain information would be the posterior medial nu- assumption that needsto be made explicit isthat all more cleus, which lies mostly medial to the ventral posterior or less contribute equally, in a sort of anatomical democ- nucleus, most of which is the first order somatosensory racy, to information flow. This same logic applied to the relay.Weclearlyneedabetterunderstandingofhowpain thalamus would produce the misconception that the lat- isprocessed by somatosensory cortex and the purpose of eral geniculate nucleus relayed brainstem, not retinal, this essay is to provide a different theoretical framework inputs to cortex (see above). that might fruitfully guide further research through this Given the nature of thalamocortical inputs, which have topic. the morphological and functional characteristics of drivers, it seems very likely that the cortico-thalamo- References cortical pathways shown in Fig. 3 are important infor- 1. Guillery RW (2003) Branching thalamic afferents link action and mation routes. It follows that understanding the rela- perception. J Neurophysiol 90:539–548 tionships of cortical areas in various functional zones 2. Guillery RW, Sherman SM (2002a) Thalamic relay functions and (e.g. visual, somatosensory and auditory among others) theirroleincorticocortical communication: Generalizationsfrom the visual system. Neuron 33:1–20 will require mapping out of all of the cortico-thalamo- 3. Guillery RW, Sherman SM (2002b) Thalamocortical pathways cortical pathways involving higher order thalamic as monitors of ongoing motor instructions. Philos Trans R Soc relays. Lond (Biol) 357:1809–1821 What, then is the function of the direct corticocortical 4. Jones EG (1985) The Thalamus. Plenum Press, New York 5. Kandel ER, Schwartz J H, Jessell TM (2000) Principles of Neural pathways?Ananswertothisimportantquestionrequires Science. McGraw Hill, New York identifying these pathways, one by one if necessary, for 6. Sherman SM, Guillery RW (2001) Exploring the Thalamus. Aca- function as driver or modulator. One extreme possibility demic Press, San Diego is that all of these pathways are modulators. However, 7. Sherman SM, Guillery RW (2002) The role of thalamus in the flow of information to cortex. Philos Trans R Soc Lond (Biol) even if some are drivers, there is an important distinction 357:1695–1708 tobemadebetweensuchputativeinformationroutesand 8. Van Essen DC, Anderson CH, Felleman DJ (1992) Information those involving higher order thalamic relays. That is, the processing in the primate visual system: an integrated systems former involve information that remains strictly within perspective. Science 255:419–423 cortex, whereas the latter involve information, perhaps involving motor commands, that is shared with various subcortical centers. Thalamocortical Module Summary and Conclusions To understand the implications of the proposal put for- wardherefortheroleofthalamusincorticocorticalcom- Definition munication, it might be helpful to contrast it with the Anatomofunctional entity comprising of thalamic cells T conventional view, and this is done in Fig. 4. In the con- and their cortical partners, interconnected by thalamo- ventionalview(Fig. 4, upper), sensory information isre- cortical and corticothalamic projections and sustaining layed from the periphery by thalamus to a primary sen- perceptual, motor and cognitive hemispheric functions. sory cortical area. From there, the information is pro- The thalamocortical loop is accompanied by a shorter cessed strictly within cortex, eventually via sensorimo- thalamoreticulothalamic loop. Every module may be tor areas to motor areas and finally this leads to a motor subdivided in a specific, or content subpart, providing output. Note that, in this view, the only role for thala- the substrate for the integration of a given function, mus is to get raw information to cortex in the first place and a non-specific, or context subpart, dealing with the and that most of thalamus, which we call higher order interactions between functional domains. relays, has no specific role to play. In the alternate view  Thalamotomy for Human Pain Relief (Fig. 4, lower) offered here, information relayed to cor- tex is, from the very beginning, corollary to motor com- mands and further corticocortical processing involves higher order thalamic relays of continuously elaborated and updated motor commands. Thus thalamus not only Thalamocortical Neurones gets information to cortex in the first place but also con- tinues to play an essential role in corticocortical com- munication. Definition This has important implications for cortical functioning Neurones located within the thalamus and projecting di- generally and also for cortical processing of pain infor- rectly to the cerebral cortex. mation more specifically. That is, the higher order tha-  Spinothalamic Projections in Rat 2432 Thalamotomy

In 1989, Lenz and collaborators (Lenz et al. 1989) Thalamotomy provided the first evidence for the presence of  low- threshold calcium spike (LTS) bursts in the thalamus Definition of patients suffering from neurogenic pain. They found A neurosurgical procedure in which a therapeutic lesion them in the somatosensory  ventral posterior (VP) is made in a specific subnucleus of the thalamus. complex, localized in and around the portion of VP  Pain Treatment, Intracranial Ablative Procedures representing the deafferented and thus painful body  Thalamotomy for Human Pain Relief part (Lenz et al. 1994). The presence of the same activi-  Thalamotomy, Pain Behavior in Animals ties was also described widely spread in and around the  Thalamus,ReceptiveFields,ProjectedFields,Human posterior part of the  central lateral nucleus (CL) of the medial thalamus (Jeanmonod et al. 1993; Jeanmonod et al. 1994; Jeanmonod et al. 1996). An example of such LTS bursting activity in CL is shown in Fig. 1 a–c), with Thalamotomy for Human Pain Relief the typical progressive increase in duration of each suc- 1 1 cessive interspike interval and the inverse relationship DANIEL JEANMONOD ,JOHANNES SARNTHEIN , 1 2 between the duration of the first interspike interval and JAIR STERN ,MICHEL MAGNIN , 1 1 the number of spikes in a burst. Furthermore, it was CHRISTOPH AUFENBERG ,ANNE MOREL 1 shown that: 1) half of the recorded neurons presented Functional Neurosurgery, Neurosurgical Clinic, LTS bursting activity, 2) only a minority (less than 1 University Hospital, Zürich, Switzerland 2 %) had somatosensory receptive fields, 3) LTS bursts INSERM, Neurological Hospital, Lyon, France displayed a theta rhythmicity, with a mean interburst [email protected] discharge rate of 4 Hz, and 4) there were no significant Synonyms differences between recordings performed in patients suffering from peripheral and central neurogenic pain. Stereotactic operation with thalamic target. First order Arecentanalysis(Sarntheinetal.,2003)ofthalamicLFP subtype: medial thalamotomy. Second order subtype: recordings in CL showed the presence of a high  theta central lateral thalamotomy. (4–8 Hz) power (Fig. 1d), correlating closely with the theta rhythmicity displayed by LTS bursts. In addition, Definition an increase in the cortical theta power was recorded by Neurophysiologicalstudiesatthecellularlevel( single EEG (Fig. 1d) and a high coherence between EEG and unit activity and  local field potentials or LFP) thalamic theta activitieswasfound (Fig. 1e). Thisunder- as well as  electroencephalographic (EEG) and scores the expected high level of functional coupling be-  magnetoencephalographic (MEG) recordings pro- tween thalamus and cortex. In Fig. 1f, EEG power spec- vide converging evidence for a thalamocortical dys- tra of patients have been averaged and compared with regulation at the origin of chronic  neurogenic pain those of controls, confirming the existence of a disease- of both peripheral and central origin. These data sug- related increase in theta power. gest an increase of low frequency thalamocortical Based on converging evidence from experimental and rhythmicity originating in disfacilitation of thalamic clinical data over the last 20 years (Llinás and Jahnsen relay neurons, followed by cortical activation due to 1982; Steriade et al. 1990; Jeanmonod et al. 1993; Jean- asymmetries of corticocortical inhibition. The process, monod et al. 1996; Jeanmonod et al. 2001; Steriade et called  thalamocortical dysrhythmia (TCD) may be- al. 1997; Llinás et al. 1999; Llinás et al. 2001), a thala- come self-sustained and thus chronic, due to recurrent mocortical concept of chronic neurogenic pain was ini- thalamoreticulothalamic and corticoreticulothalamic tially proposed at the thalamic level (Jeanmonod et al. feedback inhibition. The surgical approach presented 1993), and extended to the cortical level, with the de- here is centered on a re-establishment of a normal tha- nominationofthalamocorticaldysrhythmia(Llinásetal. lamocortical oscillatory activity using a strategically 1999). It is characterized by the following sequential set placed medial thalamic lesion, which reduces or abol- of events. ishes the TCD via low frequency desamplification and provides long term therapeutic efficiency coupled with 1. Bottom-up or top-down disfacilitation by deaf- sparing of the specific  thalamocortical modules.This ferentation of excitatory inputs onto thalamic relay physiopathological framework underscores the risks cells through a somatosensory lesion, either periph- run by any surgical procedure aiming at further reducing eral or central, is at the source of the neurogenic pain the activation of specific thalamic relay cells and thus syndrome. This results in cell membrane hyperpo- increasing thalamic disfacilitation and dysrhythmic larization. pain mechanisms. The present essay is thus focused on 2. Inthishyperpolarizedstate,deinactivationofcalcium  medial thalamotomies, more specifically on central T-channels causes thalamic relay neurons to fire LTS lateral thalamotomy (CLT). bursts at theta frequency. Thalamotomy for Human Pain Relief 2433

Thalamotomy for Human Pain Relief, Figure 1 (a, b, c) LTS bursts. (a) LTS bursting cell recorded in the posterior part of CL. Note the progressive increase in duration of each successive interspike interval (ISI). (b) Progressive increase of the ISI within the burst. (c) Logarithmic decrease of the length of the first ISI as a function of the number of spikes in the burst. (d, e, f) Spectral analysis of LFP and EEG. (d) LFP and EEG power spectra of one neurogenic pain patient (power units: μV2/Hz). (e) Coherence between EEG and LFP in the same patient. (f) Power spectra of scalp EEG recordings in 11 patients (mean age 59 +/- 13 years) and 12 healthy controls (mean age 56 +/- 10 years). Spectra were averaged over subjects.

3. These thalamic neurons impose a theta rhythmicity Characteristics to the thalamocortical modules they are part of, as demonstrated by theta power increases in both LFP Exploration of the human medial thalamus allowed the and EEG recordings. The tight functional coupling identification of a zone located in the posterior part of between thalamusand cortexisconfirmed bythe high the CL, which harbored a large majority of the recorded theta coherence between the two. This coupling is not LTS bursts (Jeanmonod et al. 1993; Jeanmonod et al. only sustained by thalamocorticothalamic, but also 1994). Considering in addition the evidence for low bythalamoreticulothalamicandcorticoreticulothala- frequency recruitment by CL stimulation (Morison and mic recurrent projections. Dempsey 1942) and surgical experience in the medial 4. Divergentthalamocortical,corticothalamicandretic- thalamus, a medial thalamic target was redefined, cen- T ulothalamic projections provide the anatomical ba- tered in the posterior part of the CL (for review, see sis for the coherent diffusion of low frequencies to Jeanmonod et al. 2001). This target aims at render- an increasing number of neighboring thalamocorti- ing the low frequency thalamocortical power increase cal modules. This phenomenon may explain the fre- subcritical by reducing theta overamplification and quentlyobserveddelaybetweentheoccurrenceofthe oversynchronization, without reducing the specific causal insult and the beginning of pain.?> and remaining unaffected non-specific thalamocortical 5. The final step consists in the activation of high fre- loops. A magnetic resonance- and microelectrode- quency (beta and gamma) cortical domains in the guided stereotactic thalamotomy in the posterior part vicinity of low frequency theta areas: constraining of the CL (central lateral thalamotomy or CLT, Fig. 2a) corticocortical GABAergic inhibitory interneurons was implemented in 96 patients (Jeanmonod et al. 2001) to theta rhythmicity may indeed reduce lateral in- suffering from chronic therapy-resistant peripheral or hibitory drive. This leads to disinhibition and thus central neurogenic pain (mean age 56 years; mean pain activation of neighboring thalamocortical modules duration before surgery 7.5 years). At a mean follow-up (edge effect), with production of pain sensation. of 3 years 9 months, 53% of the patients benefited from MEG (Llinás et al. 1999) and LFP power correlation a relief of more than 50% (Figure 2b). Patients with studies as well as LFP bicoherence data (Sarnthein et continuous pain showed only a mean relief of 20% in al. 2003) provide evidence for such a phenomenon, contrast to the 66% obtained for patients with phasic showing an increased interfrequency coherence be- or intermittent pain manifestations. Allodynia was sup- tween theta and beta domains and thus indicating a pressed in 57% of the patients. There was only a trend coupling of low and high frequency activities. for better relief in patients with peripheral neurogenic 2434 Thalamotomy for Human Pain Relief

of the limitans nucleus to avoid any intrusion into the pretectum below. From a review of the literature (Jeanmonod et al. 2001), relief percentages between 50 and 100% were obtained in averagesof 53, 47 and 53%after dorsalcolumn stimu- lation, VP stimulation and motor cortex stimulation re- spectively. These results thus come close to those ob- tained after CLT. In our study, all patients selected clin- icallyashavinganeurogenicpaindiagnosisareincluded in the results. To compare with stimulation studies, it is necessary to include in the failure percentages of these studiesthose patientswho receivedonly atemporaryun- satisfactory stimulation test, thusshowing an immediate resistance to stimulation. In many studies, quoted suc- cess rates are based only on the patients who underwent permanent implantation. A correction integrating all pa- tients with and without permanent implantation reduces pain relief percentages very significantly. The fact that CLT does not produce clinically relevant deficits suggests that the posterior part of the CL is no longer normally functional, i.e. only serves as a gener- ator of low frequencies. This is supported by the unre- sponsiveness of 99% of the recorded cells (see above) and implies a redistribution of its functions to other tha- lamic nuclei. Such a transfer may be all the more com- Thalamotomy for Human Pain Relief, Figure 2 (a) Sagittal atlas sec- tion (Morel et al., 1997) 7.2 mm distant from the ventricular border. The plete in our patients who have been operated on after horizontal scale line is aligned to the intercommissural plane, with a cross years of suffering. CLT being restricted to the medial indicating the level of the posterior commissure. Scale: 1 mm between thalamic area harboring LTS activities and exhibiting a graduations. The shaded area displays the position and extent of CLT, cen- widespread functional block leaves other medial thala- tered on the penetration track (dashed line). Abbreviations: AV, anteroven- tral; CL, central lateral; CM, centre médian; LD, lateral dorsal; Li, limitans; mic nuclei, all potential candidates for the redistribution MDpc, parvocellular part of the mediodorsal nucleus; Pf, parafascicular; of CL functions, intact. We are thus facing the paradoxi- PuM, medial pulvinar; VAmc, magnocellular part of the ventral anterior (VA) cal and conceptually intriguing situation where a lesion nucleus; VLpd and VLpv, dorsal and ventral divisions of the ventral lateral notonly producesno or only clinicallyirrelevantdeficits posterior nucleus; VM, ventral medial; VPMpc, parvocellular part of the ventral posterior medial nucleus. ZI, zona incerta. (b) Histogram displaying but also results in beneficial effects by the suppression the clinical results of the CL thalamotomy for 96 patients with a mean of a dysfunctional area (Welsh 1998). follow-up of 3 years and 9 months. The therapeutic possibilities of other medial thalamic targets, particularly the posterior complex, the medial pulvinar and the centre médian-parafascicular complex pain. An increase of continuous pain relief from 14 to seem,inourexperience,tobeinferiortothoseoftheCLT. 49% was observed when CLT was performed bilater- We have, however, not explored these areas sufficiently ally instead of only contralaterally. The CLT procedure to make a definitive statement. produced no somatosensory deficits and entailed no risk of pain increase, but only the usual vascular risk References related to the stereotactic procedure. The localization 1. Jeanmonod D, Magnin M, Morel A (1993) Thalamus and neu- and expanse of the posterior part of the CL, away from rogenic pain: physiological, anatomical and clinical data. Neu- neurologically eloquent areas, allow the placing of roreport 4:475–478 the therapeutic lesion with minimal risks for neuro- 2. Jeanmonod D, Magnin M, Morel A (1994) A thalamic concept of neurogenic pain. In: Gebhart GF, Hammond DL, Jensen TS logical functions. Extension of bleeding into adjacent (eds) Progress in Pain Research and Management. IASP Press, structures, such as the centre médian-parafascicular Seattle, pp 767–787 complex, posterior complex or medial pulvinar, does 3. Jeanmonod D, Magnin M, Morel A (1996) Low-threshold not correlate with observable deficits and could even calcium spike bursts in the human thalamus. Common phys- iopathology for sensory, motor and limbic positive symptoms. contribute to pain relief. The medial location of the CL Brain 119:363–375 target guarantees a good distance away from the VP 4. Jeanmonod D, Magnin M, Morel A et al. (2001) Surgical control and lateral spinothalamic tract and its anteroposterior of the human thalamocortical dysrhythmia: I. Central lateral tha- coordinate is posterior enough to avoid a significant en- lamotomy in neurogenic pain. Thalamus Related Syst 1:71–79 5. Lenz FA, Kwan HC, Dostrovsky JO et al. (1989) Characteris- croachment on the mediodorsal nucleus. At the ventral tics of the bursting pattern of action potentials that occurs in the limit of the target, 1–2 mm may be left intact in the area thalamus of patients with central pain. Brain Res 496:357–360 Thalamotomy, Pain Behavior in Animals 2435

6. Lenz FA, Kwan HC, Martin R et al. (1994) Characteristics of Placement of a controlled lesion in the human thalamus somatotopic organization and spontaneous neuronal activity in cannot be performed for experimental purposes. There- the region of the thalamic principal sensory nucleus in patients with spinal cord transection. J Neurophysiol 72:1570–1587 fore, studiesinvolving partial ortotalthalamotomiescan 7. Llinás R, Jahnsen H (1982) Electrophysiology of mammalian only be performed on experimental animals under con- thalamic neurones in vitro. Nature 297:406–408 trolled conditions and with strict adherence to ethical 8. Llinás RR, Ribary U, Jeanmonod D et al. (1999) Thalamocorti- guidelines for pain experimentation on animals. The ex- cal dysrhythmia: A neurological and neuropsychiatric syndrome characterized by magnetoencephalography. Proc Natl Acad Sci perimental protocol should take into consideration the USA 96:15222–15227 effects of lesions placed in different thalamic nuclear 9. Llinás R Ribary U, Jeanmonod D et al. (2001) Thalamocorti- groups known to be involved in the processing of vari- cal dysrhythmia I. Functional and imaging aspects. Thalamus ous aspects of pain. These areas can be classified under Related Syst 1:237–244 10. Morel A, Magnin M, Jeanmonod D (1997) Multiarchitectonic two major headings, the lateral and the medial nuclear and stereotactic atlas of the human thalamus. J Comp Neurol groups.Theprotocolshouldalsobebasedonspecialani- 387:588–630 malmodelssimulatingdifferentpainconditions(includ- 11. Morison R, Dempsey E (1942) A study of thalamo-cortical re- ing acute and chronic pain) and using appropriate tests lations. Am J Physiol 135:281–292 12. Sarnthein J, Morel A, von Stein A et al. (2003) Thalamic theta that allow the assessment of the different qualities of no- field potentials and EEG: high thalamocortical coherence in pa- ciception (such as mechanonociception or thermonoci- tients with neurogenic pain, epilepsy and movement disorders. ception etc.). Thalamus Related Syst 2:231–238 Despite abundant clinical literature on the thalamic syn- 13. Steriade M, Jones EG, Llinas R (1990) Thalamic oscillations and signalling. Wiley, New York drome (about 820 studies, listed in a recent Pub Med 14. Steriade M, Jones EG, McCormick DA (1997) Thalamus: Or- search), few studies have been devoted to the investiga- ganisation and Function. Elsevier, Oxford tion of the effects of various thalamic lesions on noci- 15. Welsh JP (1998) Systemic harmaline blocks associative and mo- tor learning by the actions of the inferior olive. Eur J Neurosci ceptive behavior in animals. The early work by Dela- 10:3307–3320 cour and Borst (Delacour and Borst 1972) showed that lesions of centromedian and parafascicular nuclei of the thalamus did not interfere with the escape reaction to noxious stimuli, but suppressed learning and avoidance Thalamotomy, Pain Behavior in Animals conditioning. Mitchell and Kaelber (Mitchell and Kael- ber1967)alsoshowedthatlesionofmorethan50%ofthe NAYEF E. SAADÉ,SUHAYL J. JABBUR same (plus adjacent) thalamic nuclei in cats is necessary Neuroscience Program, Faculty of Medicine, American to block the escape reaction to grid electricalshockstim- University of Beirut, Beirut, Lebanon ulation. More recently, Casey and Morrow (Casey and [email protected] Morrow 1983) showed that bilateral medial thalamic le- sions increased nociceptive responses in cats. This find- Definition ing received further confirmation by the reported effects of lesions of the nucleus submedius in rats (Roberts and Textbooks of neurology continue to regard the tha- Dong 1994). A more recent study by Norrsell and Craig lamus as an obligatory relay station for all sensory (Norrselland Craig 1999) however, reporteda mild ther- T pathways (except olfaction) on their way to the cerebral mosensory deficiency in cats subjected to  electrolytic cortex. Moreover, the thalamus has been considered to lesions placed in the various medial nuclear groups (nu- be a most important brain center for the perception of cleus submedius, posterior medial nucleus, basal ven- pain (Head and Holmes 1911). Over the last century, tral medial nucleus). It is important to note that the elec- several clinical reports described disturbed sensations trolytic lesions used can involve neuronal cell bodies in and spontaneous pain produced by thalamic lesion, a addition to passing fibers, which can have a functional pathology labeled “thalamic syndrome” (Dejerine and role different from that of the lesioned centers. Roussy 1906). Therefore, clinical and experimental Recent work from our laboratory has aimed at studying investigations have been devoted to the understanding the effects of lesions of various sizes and locations in of the mechanisms underlying sensory disturbances the thalamus on the nociceptive behavior in rats. These following thalamic lesions. lesionswereperformedbyinjectingeitherelectricalcur- rent (electrolytic) or excitotoxic substances (for selec- Characteristics tive lesion of cell bodies). Their effects were assessed on The work of Roussy (Roussy 1907) was among the first acute nociceptive reactions and on a rat  animal model attempts to reproduce the “thalamic syndrome” in an- for mononeuropathy (Saadé et al 1999). imals by controlled thalamic lesions (thalamotomies). Chronic unilateral lesions, which were either subtotal The stereotaxic method and the techniques used for the or placed in the lateral or the medial thalamus produced placement of small or large experimental lesions in the significant and persistent decreases in the mechanical thalamusareexplainedin  Post-strokepainmodel,tha- and thermal nociceptive thresholds as assessed by the lamic pain (lesion) (lesion).  paw pressure test (PP) and  hot plate (HP) tests, re- 2436 Thalamotomy, Pain Behavior in Animals

Thalamotomy, Pain Behavior in Animals, Figure 2 Summary of the effects of different types of thalamic lesions on the formalin tests performed on three groups of rats subjected to thalamic lesions as compared to a fourth intact group (sham). (top) A composite drawing showing a microscopic view Thalamotomy, Pain Behavior in Animals, Figure 1 Temporal evolution of a transverse section of a rat brain (right) and schematic drawing (left) of the effects of lesions placed in the lateral thalamus of rats. Mechanical illustrating the placement of lesions in the thalamus. (bottom) Each bar (paw pressure) and thermal (hot plate) nociceptive thresholds. The latencies represents the average nociceptive score measured during a period of of the nociceptive tests elicit a significant decrease (hyperalgesia) after the 12 min in phase I (early phase 3–15 min), or phase II (late or tonic phase lesion (time 0) when compared to the latencies of the same test observed 30–42 min) in the various groups of rats. in intact rats (control).

spectively (Fig. 1). No significant differences were no- component (the sural). This model is characterized by a ticed between the effects of electrolytic and excitotoxic persistent  allodynia (nociceptive reaction induced by lesions. Furthermore, the increased nociception was bi- non-noxious stimulus) and  hyperalgesia (increased lateral (Fig. 1) and more pronounced on supraspinally reactivity to a noxious stimulus). Both electrolytic or coordinated nociceptive tests such as the HP. Thalamic excitotoxic lesions placed either in the lateral or medial lesions also exerted differential effects on the aversive thalamic sensory nuclei produced transient decreases behavior induced by intraplantar injection of 0.05 ml of in neuropathic manifestations, which recovered their formalin 2.5%, known as the  formalin test (Dubuis- levels before thalamotomy within one or two weeks son and Dennis 1977). The most pronounced effect, ob- (Fig. 3). However, when mononeuropathy was induced served as increases in the nociceptive scores, was ob- 1 or 2 weeks after thalamic lesions, allodynia and hyper- tained with subtotal thalamic lesion (Fig. 2). algesia developed without any significant differences The effects of either lateral or medial thalamic le- (in intensity or temporal evolution) from those observed sions on the neuropathic behavior observed in a rat in animals with an intact thalamus.  animal model for mononeuropathy were also ex- Although it is difficult to produce exact simulation of amined. Neuropathy was induced by selective lesion clinical syndromes such as spontaneous pain by animal of two components (peroneal and tibial nerves) of the models, the batteries of tests employed appear to reflect sciatic nerve supplying the hind leg and sparing thethird significant changes in nociceptive reactivity in animals Thalamus 2437

Thalamotomy, Pain Behavior in Animals, Figure 3 Transient attenuation of neuropathic manifestations by electrolytic lesions in the lateral thalamic nuclei. Each lesion was performed at day zero on a group of rats subjected to mononeuropathy. Tactile allodynia and heat hyperalgesia were decreased during the first 2 weeks, after which they recovered to their pre-lesion levels. Cold allodynia was not affected (Saadé et al., unpublished data). subjected to thalamic lesions. Starting with the earliest 4. Dubuisson D, Dennis SG (1977) The formalin test: a quantitative animal experiments by Roussy in 1907, the outcome of study of the analgesic effects of morphine, meperidine and brain stem stimulation in rats and cats. Pain 4:161–174 T lesionsinsensorythalamicnucleioftenresultedineither 5. Head H, Holmes G (1911) Sensory disturbances from cerebral a decrease or no change in the nociceptive thresholds. It lesions. Brain 34:102–254 becomes necessary, therefore, to explain the resulting 6. Mitchell CL, Kaelber WW (1967) Unilateral vs bilateral medial paradox as to how a function of a center can be either thalamic lesions and reactivity to noxious stimuli. Arch Neurol 17:653–660 unaffected or exaggerated when that center is ablated? 7. Norrsell U, Craig AD (1999) Behavioral thermosensitivity after Possible answers to this question include the fact that lesions of thalamic target areas of a thermosensory spinothalamic a lesion to a nervous center can either affect, in vary- pathway in the cat. J Neurophysiol 82:611–625 ing proportions, inhibitory and excitatory mechanisms 8. Roberts VJ, Dong WK (1994) The effect of thalamic nucleus submedius lesions on nociceptive responding in rats. Pain or lead to plastic changes that adjust and compensate for 57:341–349 the insult or injury. 9. Roussy G (1907) Le syndrome thalamique. In: G. Steinheil: La  Lateral Thalamic Lesions, Pain Behavior in Animals Couche Optique. Paris 10. Saadé NE, Kafrouni AI, Saab CY et al. (1999) Chronic thalam- otomy increases pain-related behavior in rats. Pain 83:401–409 References 1. Casey KL, Morrow TJ (1983) Supraspinal pain mechanisms in the cat. In: Kitchell KL, Erickson HH (eds) Animal Pain Percep- tion and Alleviation. American Physiological Society, Bethesda, Thalamus Maryland, USA, pp 63–82 2. Dejerine J, Roussy G (1906) Le syndrome thalamique. Rev Neu- rol 14:521–532 Definition 3. Delacour J, Borst A (1972) Failure to find homology in rat, cat, and monkey for functions of a subcortical structure in avoidance ThethalamusisderivedfromtheGreekword‘Thálamos’ conditioning. J Comp Physiol Psychol 80:458–468 (bedroom, chamber). It represents the biggest structure 2438 Thalamus and Cardiac Pain of the diencephalon. Its two hemispheres are located processing (Al-Chaer et al. 1998; Willis and Westlund in the center of the brain next to the third ventricle. It 1997), studies in humans have, until recently, been lim- has reciprocal connections with the cerebral cortex and ited to intra-operative observations from patients with relays sensory signals from all senses except that of implanted deep brain stimulating electrodes (Lenz et al. olfaction to the cerebral cortex, and is also involved in 1994). However, the availability of  functional brain motor, arousal and mood functions. imaging techniques (FBI) such as  positron emis-  AnginaPectoris,NeurophysiologyandPsychophysics sion tomography (PET) and  functional magnetic  Deep Brain Stimulation resonance imaging (fMRI), has allowed visceral pain  Lateral Thalamic Pain-Related Cells in Humans researchers to confirm that the thalamus is not only an  Pain Treatment, Intracranial Ablative Procedures important relay station for visceral pain transmission,  Prefrontal Cortex, Effects on Pain-Related Behavior but may also be pivotal in the generation of symptoms  Spinothalamic Projections in Rat in several visceral pain conditions. Characteristics Thalamus and Cardiac Pain To date, information regarding the brain processing of visceral sensations and pain has been obtained fol- lowing stimulation of the esophagus, stomach, rectum,  Thalamus, Clinical Visceral Pain, Human Imaging bladder and vagina, in addition to that acquired during  dobutamine induced chest pain (Aziz et al. 1997; Hobday et al. 2001; Ladabaum et al. 2001; Matsuura Thalamus and Gastrointestinal Pain et al. 2002; Rosen et al. 1996; Whipple and Komisaruk 2002). In healthy subjects, thalamic activity has only  Thalamus, Clinical Visceral Pain, Human Imaging been reported in approximately 50% of studies, and this has been predominantly in response to noxious rather than innocuous visceral stimulation. Strigo et al. have compared the processing of visceral Thalamus and Pain and cutaneous pain in the human brain using fMRI (Strigo et al. 2003). In this study, esophageal distension Definition and contact heat stimulation of the anterior chest wall Thalamic structures (including intralaminar nuclei, were matched for subjective intensity and applied to principle sensory nucleus, nuclei posterior to it includ- healthy subjects in a counterbalanced order. Analysis ingsupra-geniculate,posterior,ventralmedial-posterior revealed that whilst differences were seen in cortical nucleus) that have pain-related activity, as identified by regions such as the anterior insula, a common pain anatomic and physiologic studies in primates. neural network was activated encompassing the second  Pain Treatment, Motor Cortex Stimulation somatosensory cortex, posterior parietal cortex, basal ganglia and thalamus. The authors concluded that the similar activations seen within these regions implicate their function in the identification of a stimulus as Thalamus and Visceral Pain (Positron painful, rather than in the differentiation between the Emission Tomography or Functional nature of painful stimuli (Strigo et al. 2003). Magnetic Resonance Imaging) In a PET study that examined the effect of increasing in- tensity of gastric distension on cortical and sub-cortical  Thalamus, Clinical Visceral Pain, Human Imaging activation, Ladabaum etal.reported significantthalamic activity only at the highest distension volumes, which produced a noxious stimulus. Peak activations were noted bilaterally in the ventral posteriolateral (VPL) Thalamus and Visceral Pain Processing nuclei and in the left dorsomedial nuclei (Ladabaum et (Human Imaging) al. 2001) leading the authors to conclude that noxious gastric stimulation activates both the lateral and medial ANTHONY R. HOBSON,QASIM AZIZ pain systems. Section of GI Sciences, Hope Hospital, University of The ability to non-invasively map the neuroanatomy Manchester, Manchester, UK of the visceral pain matrix has lead to several re- [email protected] searchers embarking on clinical studies in patients with  functional gastrointestinal disorders, predom- Definition inantly in patients with  irritable bowel syndrome Whilst there is ample evidence from animal studies (IBS). Patients with IBS commonly report heightened to support the role of the thalamus in visceral pain perception of rectal distension ( visceral hypersensi- Thalamus and Visceral Pain Processing (Human Imaging) 2439 tivity), and the aim of these studies has been to identify was seen; however, thalamic activity was still evident. objective neural correlates of visceral hypersensitivity. The authors concluded that the thalamus acted as a Whilst the heterogeneity of the IBS population has gateway for afferent visceral pain signals; however, meant that results from group imaging data have been cortical activity was needed to bring this to a level of inconsistent, several groups have shown increased conscious perception. Further evidence to support this thalamic activation in response to noxious rectal dis- has been provided by additional studies in patients with tension (Mertz et al. 2000; Verne et al. 2003; Yuan et silent ischemia and  syndrome X (Rosen et al. 1996, al. 2003). The thalamic regions of interest identified 2002). in these studies encompassed the VPL and dorsome- In summary, painful visceral stimuli produce bilateral dial nuclei. The limited spatial resolution of the fMRI activation of the thalamus incorporating the regions of imaging techniques used in these studies meant that it the VPL and dorsomedial nuclei. Heightened activation was not possible to comment on activation of specific of these regions has been associated with aberrant pain thalamic nuclei, and thus no comment could be made processing in patients with gastrointestinal and cardiac on the specific contribution of the sensory and affec- disease. As the spatial resolution of FBI techniques im- tive dimensions of pain. Future clinical studies using proves,itwillbepossibletostudythethalamusingreater high resolution imaging of the thalamus may be able detail shedding further light on its role in visceral pain to provide more information regarding the contribution processing. of different thalamic regions to aberrant visceral pain processing in IBS. References Perhaps the most dramatic evidence to support the role of the thalamus in aberrant visceral pain processing 1. Al-Chaer ED, Feng Y, Willis WD (1998) A Role for the Dor- sal Column in Nociceptive Visceral Input into the Thalamus of comes from studies by Rosen et al. in patients with Primates. J Neurophysiol 79:3143–3150 various forms of  angina pectoris (Rosen et al. 1996, 2. Aziz Q, Andersson JL, Valind S et al. (1997) Identification of Hu- 2002). A previous case report from 1994 had reported man Brain Loci Processing Esophageal Sensation using Positron Emission Tomography. Gastroenterology 113:50–59 that microstimulation of the VPL induced angina like 3. Hobday DI, Aziz Q, Thacker N et al. (2001) A Study of the symptoms in a single patient, which was not coincident Cortical Processing of Ano-Rectal Sensation using Functional with changes in cardiovascular function, strongly im- MRI. Brain 124:361–368 plicating the VPL in visceral and referred pain (Lenz 4. Ladabaum U, Minoshima S, Hasler WL et al. (2001) Gastric Distention Correlates with Activation of Multiple Cortical and et al. 1994). Rosen followed this up with a PET study Subcortical Regions. Gastroenterology 120:369–376 in which he measured brain activity during intravenous 5. Lenz FA, Gracely RH, Hope EJ et al. (1994) The Sensation of dobutamine infusion in patients with coronary artery Angina can be Evoked by Stimulation of the Human Thalamus. disease and active angina (Rosen et al. 1994). These Pain 59:119–125 6. Matsuura S, Kakizaki H, Mitsui T et al. (2002) Human Brain Re- data revealed that dobutamine induced angina was gion Response to Distention or Cold Stimulation of the Bladder: associated with bilateral activation of the thalamus, A Positron Emission Tomography Study. J Urol 168:2035–2039 in addition to activation of a number of higher corti- 7. Mertz H, Morgan V, Tanner G et al. (2000) Regional Cerebral cal structures. Following the cessation of dobutamine Activation in Irritable Bowel Syndrome and Control Subjects with Painful and Non-Painful Rectal Distension. Gastroenterol- T infusion, symptoms ceased and no cortical activity ogy 118:842–848 8. Rosen SD, Paulesu E, Frith CD et al. (1994) Central Nervous Pathways Mediating Angina Pectoris. Lancet 344:147–150 9. Rosen SD, Paulesu E, Nihoyannopoulos P et al. (1996) Silent Ischemia as a Central Problem: Regional Brain Activation Com- pared in Silent and Painful Myocardial Ischemia. Ann Intern Med 124:939–949 10. Rosen SD, Paulesu E, Wise RJ et al. (2002) Central Neural Con- tribution to the Perception of Chest Pain in Cardiac Syndrome X. Heart 87:513–519 11. Strigo IA, Duncan GH, Boivin M et al. (2003) Differentiation of Visceral and Cutaneous Pain in the Human Brain. J Neurophysiol 89:3294–3303 12. Verne GN, Himes NC, Robinson ME et al. (2003) Central Rep- resentation of Visceral and Cutaneous Hypersensitivity in the Irritable Bowel Syndrome. Pain 103:99–110 13. Whipple B, Komisaruk BR (2002) Brain (PET) Responses to Vaginal-Cervical Self-Stimulation in Women with Complete Spinal Cord Injury: Preliminary Findings. J Sex Marital Ther 28:79–86 14. Willis WD, Westlund KN (1997) Neuroanatomy of the Pain Sys- Thalamus and Visceral Pain Processing (Human Imaging), Figure 1 tem and of the Pathways that Modulate Pain. J Clin Neurophysiol This image shows bilateral activation of the thalamus following painful 14:2–31 esophageal balloon distension. In addition, activity is also seen in the pri- 15. Yuan YZ, Tao RJ, Xu B et al. (2003) Functional Brain Imaging mary / secondary somatosensory cortex and insula. These four regions in Irritable Bowel Syndrome with Rectal Balloon-Distention by are robustly activated following noxious visceral stimulation. using fMRI. World J Gastroenterol 9:1356–1360 2440 Thalamus, Clinical Pain, Human Imaging

The result seems paradoxical since one would naturally Thalamus, Clinical Pain, Human Imaging associate decreased thalamic activity with decreased A. VANIA APKARIAN pain and not the other way. We argue below that this Feinberg School of Medicine, Department of observation is consistent with the notion that chronic Physiology, Northwestern University, Chicago, IL, pain conditionsaremoreemotionalstatesand henceless USA sensory; as a result they may involve less spinothalamic [email protected] activation and enhanced activations through pathways more directly accessing emotional regions of the brain. Synonyms The first clinical pain study was done in 5 patients with chronic cancer pain, where brain activity as determined Chronic pain; BOLD activity; voxel-based morphome- by PET was compared between them and normal sub- try; Gray Matter Density jects before and after high cervical cordotomies that Definition resulted in significant pain relief (Di Piero et al. 1991). The main outcome of the study was the observation Non-invasive human brain imaging provides the oppor- that thalamic activity was low in the patients during tunitytoexaminecentralprocessesthatmaybecritically chronic pain and normalized after the cordotomy. At involved in the induction and/or maintenance of clinical least another 5 studies report that chronic clinical chronic pain conditions. Such studies point to the notion pain conditions are associated with decreased baseline that the thalamus shows reduced signaling and reduced activity or decreased stimulus related activity in the graymatter,suggestingthattheregionisatleastanactive thalamus. A SPECT blood flow study (Fukumoto et al. player in chronic pain conditions. 1999) has shown a strong relationship between time of onset of CRPS symptoms and thalamic activity. The Characteristics ratio between contralateral and ipsilateral thalamic per- The advent of non-invasive brain imaging technologies fusion was larger than 1.0, indicating hyperperfusion, affords a unique opportunity for unraveling brain pro- for patients with symptoms for only 3–7 months and cesses that may be critical in induction and/or mainte- smaller than 1.0, indicating hypoperfusion, for patients nance of clinical chronic pain conditions. Such studies with longer-term symptoms (24–36 months), with a have the potential for replacing speculations, psychoso- correlation coefficient of 0.97 (normal subjects had a cial interpretations and accusations of patients by dub- thalamic perfusion ratio of about 1.0). These results bing them malingerers and other such labels, by physio- strongly imply that the thalamus undergoes adaptive logicalparametersthatcharacterizetheseconditionsand changes in the course of CRPS. Thus, it can be asserted then hopefully lead to new, more science based devel- that thalamic activity for pain in chronic clinical condi- opment of therapies. Here we briefly discuss the current tions is different from that for acute painful stimuli in understanding of the role of the thalamus in clinical pain normal subjects. states based on human brain imaging studies. Proving long-term reorganization of the CNS is hard Brain activity as determined by  PET or  fMRI has with functional imaging, since one cannot disentangle established a reproducible pattern of cortical activity reorganization from modulation of responses due to the associated with acute or experimental painful condi- presence of the condition, for example in chronic pain. tions. A recent meta-analysis, of such studies over the On the other hand, examination of brain chemistry by last 15 years estimated that the incidence of reporting of  MRS indicates changes in various metabolites, most thalamic activity in experimental pain conditions is 84% of which are not affected by the current cognitive state (16/19 studies) in PET studies and 81% (13/16 studies) of the person. Thus, such measures document long-term in fMRI studies (Apkarian et al. 2005) (incidence here changes more readily. The limitation of the technique is the ratio of the number of studies where the area was regards the specific chemicals that can be detected (the investigated in contrast to the number of studies where specific functions of many of which remain unclear), the area was reported to be activated). In contrast to this and the need for regional imaging which limits the value, when the incidence of thalamic activity is exam- spatial extent of the measurement (Salibi and Brown ined in brain imaging studies in clinical pain conditions 1998). One such study examined thalamic metabolites the incidence is 59% (16/27 PET,  SPECT and fMRI in chronic back pain patients and observed no changes studies combined). The conditions included in the clin- in comparison to healthy subjects, although there were ical cases are cancer pain, cluster headache, migraine, decreased measures for multiple metabolites in the cardiac pain, irritable bowel syndrome, fibromyalgia, prefrontal cortex (Grachev et al. 2000). Another similar CRPS, phantom pain and mono- or poly-neuropathies study examined thalamic metabolites (Pattany et al. (Apkarian et al. 2005). Contrasting the incidence of 2002) in patients with chronic neuropathic pain after thalamic activity in normal subjects to clinical pain spinal cord injury and did see decreased metabolites in conditions indicates a borderline significant decrease the thalamus and observed a negative correlation be- in clinical conditions (p = 0.09, Fisher’s exact test). tween pain intensity and concentration in the thalamus. Thalamus, Clinical Visceral Pain, Human Imaging 2441

Since a decreased concentration of N-acetyl-aspartate ent types of clinical pains. The extent to which this has been reported in most neurodegenerative condi- reorganization contributes to such conditions remains tions, it is reasonable to conclude that the observation unclear. More importantly, these observations strongly of decreased N-acetyl-aspartate in the chronic spinal suggest that at least part of this reorganization may be a cord injury patients suggests that the condition is associ- consequence of neuronal death and hence irreversible, ated with a neurodegenerative process in the thalamus. pointing to the urgency for further elaborating these This idea was tested directly in a morphometric study. details and for more effective therapeutic approaches The gray matter density of chronic back pain patients for these conditions. was contrasted with age and gender matched normal subjects using high resolution anatomical MRI. The References results indicate that the thalamus gray matter density, 1. Apkarian AV, Sosa Y, Sonty S et al. (2004) Chronic back pain mainly on the right, is significantly lower in density in is associated with decreased prefrontal and thalamic gray matter density. J Neurosci 24:10410–10415 the chronic back pain patients (Apkarian et al. 2004). 2. Apkarian AV, Bushnell MC, Treede RD et al. (2005) Human The mechanisms inducing this atrophy remain to be brain mechanisms of pain perception and regulation in health determined, as well as the extent of its reversibility and and disease. Eur J Pain 9:463-84 its impact on information processing in the thalamus. 3. Derbyshire SW (1999) Meta-Analysis of Thirty-Four Indepen- dent Samples Studied Using PET Reveals a Significantly Atten- However, the observation clearly implies that the thala- uated Central Response to Noxious Stimulation in Clinical Pain mus is undergoing long-term reorganization due to the Patients. Curr Rev Pain 3:265–280 presence of the pain condition. It is also possible that 4. Di Piero V, Jones AK, Iannotti F et al. (1991) Chronic pain: a some of this reorganization has a genetic component PET study of the central effects of percutaneous high cervical cordotomy. Pain 46:9–12 that may predispose these subjects to develop chronic 5. Fukumoto M, Ushida T, Zinchuk VS et al. (1999) Contralateral pain. Thus, there are more questions raised than an- thalamic perfusion in patients with reflex sympathetic dystrophy swered. Fortunately, these questions can be answered syndrome. Lancet 354:1790–1791 in future studies and should provide a more accurate 6. Grachev ID, Fredrickson BE, Apkarian AV (2000) Abnormal brain chemistry in chronic back pain: an in vivo proton magnetic understanding of the role of the thalamus in chronic resonance spectroscopy study. Pain 89:7–18 pain conditions. 7. Hunt SP, Mantyh PW (2001) The molecular dynamics of pain Decreased brain responses to painful stimuli in clinical control. Nat Rev Neurosci 2:83–91 pain conditions have been observed in other meta- 8. Pattany PM, Yezierski RP, Widerstrom-Noga EG et al. (2002) Proton magnetic resonance spectroscopy of the thalamus in analyses of the literature (Derbyshire 1999; Peyron et patients with chronic neuropathic pain after spinal cord injury. al. 2000), and interpreted as evidence for a generalized AJNR Am J Neuroradiol 23:901–905 decrease in brain activity in such patients. However, 9. Peyron R, Laurent B, Garcia-Larrea L (2000) Functional imaging of brain responses to pain. A review and meta-analysis (2000). when the incidence of prefrontal cortical activity is Neurophysiol Clin 30:263–288 examined, one observes increased incidence of activat- 10. Salibi N, Brown MA (1998) Clinical MR spectroscopy. Wiley- ing this region in chronic pain patients in contrast to Liss, New York normal subjects. In normal subjects, prefrontal cortex is activated in 55% (23/42) of functional imaging studies T for pain, while in pain patients this rate increases to Thalamus, Clinical Visceral Pain, Human 81% (21/26, p =0.04, Fisher’s exact statistics). Thus, in chronic pain patients, decreased thalamic activity Imaging seems to be accompanied by increased prefrontal corti- URI LADABAUM cal activity. This implies a switch of nociceptive inputs Division of Gastroenterology, University of California, away from spinothalamic afferents and enhanced no- San Francisco, CA, USA ciceptive inputs through brainstem prefrontal cortical [email protected] regions. This has been suggested in animal models of neuropathic pain (Hunt and Mantyh 2001), based Synonyms on the response changes observed in spinal cord neu- rons following neuropathic injury. The shift suggests Thalamus and Cardiac Pain; Thalamus and Gastroin- that chronic clinical pain conditions are more emo- testinal Pain; Thalamus and Visceral Pain (Positron tional/cognitive than sensory. Whether the thalamic Emission Tomography or Functional Magnetic Reso- atrophy observed in back pain patients directly con- nance Imaging) tributes to this shift remains to be determined. It is at least consistent with the model. Definition Overall, multiple lines of investigations regarding the Visceral pain arises from the internal organs, such as the involvement of the thalamus in clinical pain conditions heart and the gastrointestinal tract. In contrast, somatic imply that the region actively reorganizes in such con- pain arises from the skin and deeper tissues, including ditions. It should be emphasized that most probably muscle. The central nervous system regions activated by the details of this reorganization are specific to differ- visceral pain in humans, including the thalamus, have 2442 Thalamus, Clinical Visceral Pain, Human Imaging been studied non-invasively with  positron emission Esophageal Stimulation tomography (PET) and  functional magnetic reso- An early PET study of the cerebral regions involved in nance imaging (fMRI), functional imaging techniques esophageal sensation found bilateral activations along that measure increased regional cerebral blood flow as the central sulcus, insulae, and frontal and parietal a marker of neuronal activation. operculum during non-painful esophageal distension and more intense activations in these regions as well Characteristics as additional activation in the right anterior insular cortex and the anterior cingulate gyrus during painful Thalamic activation (defined asa statistically significant distension (Aziz et al. 1997). Thalamic activation was increase in regional blood flow during the condition of not detected. interest) has been reported in many but not all functional Subsequently, a fMRI study examined the cerebral cerebral imaging studies of visceral pain in humans. The cortical response to esophageal distension or acid per- cerebral representation of visceral pain was first studied fusion (Kern et al. 1998). Acidification and distension by inducing angina in humans, and later by distending generally resulted in activations of Brodmann’s areas gastrointestinal viscera to induce pain. A recent system- 7, 23, 30, 32, insula, operculum and anterior cingulate atic review that included inspection of published images cortex. Although the activated regions were similar, by the author in addition to the resultsexplicitly reported the temporal characteristics of the activation were dif- by investigators found evidence for thalamic activation ferent (slower for acidification). Significant thalamic with angina, noxious esophageal stimulation, gastric activation was again not detected. distension and noxious lower gastrointestinal disten- The cortical processing of distal and proximal esopha- sion in healthy volunteers and patients with  irritable geal sensation has been compared using fMRI (Aziz et bowel syndrome (IBS) (Derbyshire 2003). al. 2000). Among other differences, proximaldistension was localized precisely to the upper chest and activated Cardiac Ischemia and Angina the left primary somatosensory cortex, whereas distal A pioneering  PET study reported the central nervous distension was perceived diffusely over the lower chest system pathways mediating  dobutamine-induced and activated the junction of the primary and secondary angina in patients with coronary artery disease (Rosen somatosensory cortices bilaterally. Significant thalamic et al. 1994). Compared to the resting state, regional activation was not reported. blood flow increased during angina in a number of The cerebral processing of visceral and cutaneous cerebral structures, including increases of 2.7% in the pains were compared using distal esophageal disten- left thalamus and 3.7% in the right thalamus. After sion and application of heat to the chest during cerebral the resolution of angina, thalamic activity remained fMRI scanning (Strigo et al. 2003). Painful esophageal significantly increased, whereas the cortical activity distension and painful heat stimulation both induced associated with angina was no longer detected. The statistically significant thalamic activation on the left authors suggested that the thalamus receives input from and non-significant activation on the right. Overall, a the heart during angina and continues to receive such similar neural network was activated with visceral and input even when angina is no longer felt, with this less somatic stimulation, but notable differences were also intense signal not being transmitted to the cerebral apparent that probably relate to the differences in the cortex and therefore not associated with conscious experience of visceral and cutaneous pain. perception. Thedifferentresultsamongthesestudiesprobablyrelate Cerebral PET imaging was then used to gain insight into to differences in experimental design, study population the problem of  silent myocardial ischemia (Rosen et and chance. Regional cerebral blood flow changes with al. 1996). Cerebral activation patterns were compared “activation”aregenerallysmall(afewpercent).Because betweenpatientswithstress-inducedanginaandpatients the thalamus is a major relay and processing station be- with stress-induced myocardial ischemia but no angina. tween the periphery and the cortex and basal ganglia and During myocardial ischemia, significant left thalamic because thalamic activation has been reported in a sub- activation was detected in patients with angina and bi- stantial proportion of all available visceral pain studies lateral thalamic activation was detected in patients with in humans, itislikely thatthe lack ofsignificantthalamic silent ischemia. However, much more extensive cortical activation in the first three studies reflects the limitations activation was seen in those with angina. Because thala- of the available techniques. micactivationwasseeninbothgroupsofpatients,theau- thors concluded that  silent myocardial ischemia can- Gastric Stimulation not be explained by peripheral nerve dysfunction. They Cerebral PET imaging during increasing levels of proposed that abnormal central processing of afferent gastric distension detected progressive increases in pain signals (possibly abnormal gating at the level of activation in multiple cortical and subcortical regions, the thalamus), may contribute to the pathophysiology of including the thalami, insulae, anterior cingulate cortex, silent myocardial ischemia. periaqueductal gray matter and cerebellum (Ladabaum Thalamus, Clinical Visceral Pain, Human Imaging 2443 et al. 2001). Statistically significant activation centered both rectal and somatic stimulation (Verne et al. 2003). in the right ventral posterolateral (VPL) nucleus of However, thalamic activation has not been detected in the thalamus was detected with distension producing all subsequent studies (Berman et al. 2002). As with threshold pain as well as distension producing moder- the esophageal stimulation studies that failed to de- ate pain. Statistically significant activations centered tect thalamic activation, it seems likely that the lack in the VPL and dorsomedial (DM) nuclei of the left of significant thalamic activation in some rectal dis- thalamus were detected with distension producing tension studies reflects the limitations of the available moderate pain. The VPL nucleus is a key component technology. of the lateral pain system, which is believed to subserve the sensory-discriminative component of pain and the Summary DM nucleus is part of the medial pain system, which The thalamus is a major relay and processing station be- is believed to mediate the affective-motivational com- tween the peripheral nervous system and higher centers ponent of pain. The identification of precise thalamic in the central nervous system. It would be anticipated nuclei as the regions of peak activation must be inter- that cerebral functional imaging studies using PET or preted with caution given the spatial resolution limits fMRI in humans would detect thalamic activation dur- of PET. ing visceral pain. Many such studies have indeed de- tected thalamic activation. The results include thalamic Rectosigmoid Stimulation activation during myocardial ischemia with or without A pioneering PET study of visceral sensation in healthy angina and after the resolution of angina and thalamic volunteers and patients with IBS found thalamic acti- activation during distal esophageal distension, gastric vation of borderline significance during rectal disten- distension and rectal distension. However, not all stud- sion in healthy volunteers (Silverman et al. 1997). An ies of functional cerebral imaging during gastrointesti- early fMRI study detected activation in numerous re- nalvisceraldistensionhavedetectedthalamicactivation. gions including the anterior cingulate, prefrontal, insu- These seemingly inconsistent results are probably due lar and sensorimotor cortices during rectal distension in to limitations in the sensitivity of the available technol- healthy volunteers, but no thalamic activation was de- ogy. tected (Baciu et al. 1999). A larger study of healthy volunteers (16) and IBS pa- References tients (18) using fMRI during rectal distension reported 1. Aziz Q, Andersson JL, Valind S et al. (1997) Identification of increased activity in the anterior cingulate, prefrontal, human brain loci processing esophageal sensation using positron and insular cortices, as well as increased thalamic activ- emission tomography. Gastroenterology 113:50–59 ity in nearly all subjects(Mertz et al. 2000). Incontrast to 2. Aziz Q, Thompson DG, Ng VW et al. (2000) Cortical pro- cessing of human somatic and visceral sensation. J Neurosci earlier results (Silverman et al. 1997), this study found 20:2657–2663 comparable patterns of activation in healthy volunteers 3. Baciu MV, Bonaz BL, Papillon E et al. (1999) Central process- and IBS patients, but greater activation of the anterior ing of rectal pain: a functional MR imaging study. AJNR Am J cingulate cortex during painfulcomparedto non-painful Neuroradiol 20:1920–1924 4. Berman SM, Chang L, Suyenobu B et al. (2002) Condition- T stimulation only in IBS patients. specific deactivation of brain regions by 5-HT3 receptor antag- An intriguing study examined cerebral activation during onist Alosetron. Gastroenterology 123:969–977 subliminal visceral stimulation caused by rectal disten- 5. Derbyshire SW (2003) A systematic review of neuroimaging data sion (Kern and Shaker 2002). Cerebral activation during during visceral stimulation. Am J Gastroenterol 98:12–20 6. Kern MK, Shaker R (2002) Cerebral cortical registration of sub- subliminal distension was generally bilateral in regions liminal visceral stimulation. Gastroenterology 122:290–298 including the sensory/motor, parieto-occipital, anterior 7. Kern MK, Birn RM, Jaradeh S et al. (1998) Identification and cingulate, prefrontal and insular cortices. Distension to characterization of cerebral cortical response to esophageal mucosal acid exposure and distention. Gastroenterology liminal (threshold sensation) and supraliminal (above 115:1353–1362 threshold sensation) levels activated regions similar to 8. Ladabaum U, Minoshima S, Hasler W et al. (2000) Gastric disten- those activated with subliminal stimulation, but the vol- tion correlates with activatin of multiple cortical and subcortical ume of cortical activity increased with the stimulus in- regions. Gastroenterology 120:369–376 9. Mertz H, Morgan V, Tanner G et al. (2000) Regional cerebral tensity. In contrast to studies of myocardial ischemia in activation in irritable bowel syndrome and control subjects which thalamic activity was detected even after resolu- with painful and nonpainful rectal distention. Gastroenterology tion of angina (Rosen et al. 1994; Rosen et al. 1996), 118:842–848 thalamic activation was not detected in this study of sub- 10. Rosen SD, Paulesu E, Frith CD et al. (1994) Central nervous pathways mediating angina pectoris. Lancet 344:147–150 liminal rectal sensation. 11. Rosen SD, Paulesu E, Nihoyannopoulos P et al. (1996) Silent Some subsequent studies involving rectal distension ischemia as a central problem: regional brain activation com- have reported significant thalamic activation (Verne pared in silent and painful myocardial ischemia. Ann Intern Med et al. 2003; Yuan et al. 2003), including greater acti- 124:939–949 12. Silverman DH, Munakata JA, Ennes H et al. (1997) Regional vation in the thalamus and multiple other regions in cerebral activity in normal and pathological perception of visceral IBS patients compared to healthy volunteers during pain. Gastroenterology 112:64–72 2444 Thalamus, Dynamics of Nociception

13. Strigo IA, Duncan GH, Boivin M et al. (2003) Differentiation of thalamic neurons induced by states of peripheral persis- visceral and cutaneous pain in the human brain. J Neurophysiol tent pain. Several studies have shown that in conditions 89:3294–3303   14. Verne GN, Himes NC, Robinson ME et al. (2003) Central rep- of hyperalgesia or allodynia the neurons in the resentation of visceral and cutaneous hypersensitivity in the ir- ventrobasal complex of the lateral thalamus have en- ritable bowel syndrome. Pain 103:99–110 hanced responsiveness, i.e. they have lower activation 15. Yuan YZ, Tao RJ, Xu B et al. (2003) Functional brain imaging in thresholds for both thermal and mechanical stimuli and irritable bowel syndrome with rectal balloon-distention by using fMRI. World J Gastroenterol 9:1356–1360 larger peripheral receptive fields and continue to dis- charge spontaneously for long periods after cessation of the noxious stimulation (Guilbaud et al. 1990; Sherman et al. 1997). Ultimately, it is difficult to determine to Thalamus, Dynamics of Nociception what extent this functional plasticity corresponds to a VASCO GALHARDO change within the thalamic networks or if the enhanced Institute of Histology and Embryology, Faculty of thalamic activity is instead simply a consequence of Medicine of Porto, University of Porto, Porto, Portugal the enhanced somatosensory information generated at [email protected] spinal levels during chronic pain. One strong piece of evidence for the occurrence of plasticity at the thala- Synonyms mic level is that painful sensations are evoked more frequently by microstimulation of the lateral thalamus Thalamic plasticity; Thalamic Reorganization; sensiti- in patients with chronic neuropathic pain than in pa- zation tients with non-painful movement disorders (Davis et al. 1996). Further microstimulation studies suggest that Definition in neuropathic pain patients, thalamic areas usually Thedynamicsofthethalamicresponsestonoxiousstim- signaling thermal non-painful discrimination are now uli are the signature of neural mechanisms that make evoking painful sensations when stimulated (Lenz et the responses not rigid and immutable, since they reflect al. 1998). both the nature of the incoming afferent signal and the It is very tempting to assume that the enhanced sensory internal state of the neuronal populations that process activity corresponds to a progressive change of thala- nociceptive signals. micnociceptive-specificneuronsintothewide-dynamic range category, as was implied in some studies (Guil- Characteristics baud et al. 1990). However, multielectrode recordings Somatosensory noxious information is processed by the lasting several hours in the rat somatosensory thalamus thalamus in a complex manner that is still little under- (Brueggemannet al. 2001) showed that immediately af- stood. Far from being a simple relay station for painful ter a nerve lesion no rigid pattern of change between cell stimuliontheirwayfromtheperipherytothecortex,tha- types could be found (Fig. 1). Although the results from lamic neurons integrate and modulate the pain signals in multielectrode studies show immediate fluctuations in a dynamic way. This implies that the modulation itself responseproperties,theydonotshowaclearnetincrease is the result of the instantaneous status of the thalamic in nociceptive responses in the affected portion of the neuronalnetwork.Byaddressingthetopicofthedynam- lateral thalamus. ics of thalamic responses we acknowledge the fact that Deafferentation-Induced Plasticity the arriving nociceptive information will not always be processed by the thalamic neural networks in exactly the Paradoxically, just as the enhanced somatosensory in- same manner, since the functional properties of the pro- formation leads to a sensitization of thalamic networks, cessingneuralnetworkswillchangeovertime,reflecting the decrease in somatosensory information arriving at the history of the incoming signals. the thalamus due to peripheral nerve lesions also leads The factors that affect the status of the processing neural to higher levels of pain sensitivity. This is probably due networks may be extrinsic to the thalamus – meaning to the fact that both the functional loss of afferents by thattheyarecausedbythequalitiesofthepastandimme- peripheral lesions and the functional gain of afferents diate afferent information - or intrinsic – meaning that by peripheral  hyperalgesia lead to similar net effects; they are the result of the status of the thalamus, namely some regions of the thalamus are suddenly more active the occurrence of population  oscillations. than their neighbors and this spatial imbalance causes This brief essay will review four key aspects of nocicep- a regional peak of activity that leads to somatosensory tive information processing dynamics within the thala- hypersensitivity.  Deafferentation studies also reveal mus. a crosstalk between somatosensory modalities in which both the disruption of thick myelinated non-nociceptive Sensitization of the Thalamus fibers leads to altered pain perception and the disruption The most basic aspect of thalamic somatosensory of unmyelinated high-threshold  CFiberleads to al- dynamics is the change in the response properties of tered tactile perception. A recent multielectrode study Thalamus, Dynamics of Nociception 2445

have distinct velocity and synchrony characteristics that would result in complex spatiotemporal patterns, diffi- cult to interpret and predict. By the same token, it has been conclusively shown that for fine tactile discrimination also, the spatiotemporal maps are complex to determine and reorganize after pe- ripheral  deafferentation and that distributed coherent activity in the thalamus plays a key role in the encoding of somatosensory signals (Nicolelis 1997).

Thalamic Oscillations and Pain Processing Thethalamusisknowntohavetwomodesoffiring:tonic mode, in which neurons fire single action potentials and bursting mode, in which neurons fire in rhythmic rapid bursts of several action potentials. Traditionally, thalamic bursts were associated with non-aware states, while tonic mode was associated with alert states, al- though thissimple scheme hasbeen questioned in recent Thalamus, Dynamics of Nociception, Figure 1 Changes in classifica- tion of lateral thalamic neurons at the beginning (Before, before sciatic studies (Nicolelis and Fanselow 2002). High-frequency nerve ligation) and at the end of the experiments (After, after nerve liga- spike bursts are one of the most characteristic features tion). Horizontal lines indicate no change; diagonal lines indicate changes in observed in the thalamus following  deafferentation neuronal class. Abbreviations: Ø, unresponsive neurons; LT, Low-threshold neurons; WDR, wide-dynamicrangeneurons; NS, nociceptive-specificneu- by lesion of peripheral nerves, dorsal roots or the spinal rons (Figure taken from Brueggemann et al. 2001). cord (Albe-Fessard et al. 1985; Guilbaud et al. 1990). In the thalamus, spike bursts have been described with very specific membrane physiology and have been in the rat lateral thalamus (Katz et al. 1999) showed that shown to function normally to synchronize activity of the silencing of  c-fibers after perioral capsaicin injec- neurons both within and between thalamic nuclei as tions changed the pattern of sensitivity to tactile deflec- well as between the thalamus and cortex. In human tha- tion of the whiskers, resulting in “unmasking” of new lamic recordings performed during surgery (Lenz et al. tactile responses. 1989), a characteristic series of spontaneous short high frequency spike trains (3–8 action potentials occurring Spatiotemporal Dynamics in the Thalamus at 60–160 Hz) or spike bursts was found in long-term Several studies have shown novel properties in the tha- para- and tetraplegics. These bursts repeat themselves lamic integration of nociceptive signals, in both space in low-frequency  oscillations in pain patients and the and time domains. Finding spatiotemporal patterns of clinical condition has been termed  thalamocortical coherence in the activity of neuronal populations in the dysrhythmia (Llinás et al. 1999). thalamus during the processing of pain will help unravel Significance has been assigned to changes in the tem- T the intrinsic organization of the processing units within poral patterns of activity in thalamic neurons following the lateral thalamus. The use of multielectrode arrays deafferentation because spike bursts in pain patients are with precise spatial arrangements showed that the func- especially concentrated in regions of the lateral thala- tional connectivity between pairs of neurons depends mus representing the painful part of the body. In Fig. 2 on the distance separating them; neighboring nocicep- wepresentanexampleofsuchaburstactivity.Thefigure tive neurons tend to be positively correlated, while most is taken from Weng et al. (2000) where the authors re- negative correlations in evoked spike timings occur be- port that thalamic wide-dynamic range neurons (but not tween neurons separated by more than 50 μm (Apkar- the low-threshold neurons) of monkeys partially deaf- ian et al. 2000). Interestingly, the spatial maps of evoked ferentedbyspinalcordlesionsshowedenhancedactivity spike coherence between pairs of neurons were differ- compared with the same types of cells in thalamus with ent for noxious and non-noxious stimulations, with tac- intact innervation; both the spontaneous and evoked dis- tile stimuli inducing almostno inhibitory spatialeffects. charges of the cells were altered, so that there was an in- The results of that study also suggest that in the primate creasedincidenceofspike-burstsincellsofdeafferented thalamus, nociceptive and non-nociceptive neurons are thalamus. clustered separately in a lattice manner. This spatial ar- Recently, the importance of this abnormal thalamic rangement of the lateral thalamus would have profound firing for the genesis of chronic central pain has been implications for the spatiotemporal dynamics of thala- challenged by the finding of no differences between mic function, since nociceptive clusters would receive the number of oscillating neurons in the thalamus of spinothalamic afferents while non-nociceptive clusters allodynic versus non-allodynic rats with spinal cord would receive mainly dorsal column afferents and both injury (Gerke et al. 2003), suggesting that  thalamic 2446 Thalamus Lesion

Thalamus, Dynamics of Nociception, Figure 2 Brush stimuli evoke oscillatory activity in the lateral thalamus of animals with complete sectioning of the anterolateral spinal quadrant (Figure taken from Weng et al. 2000). dysrhythmia is linked to cord injury but not to the pres- 12. Nicolelis MAL, Fanselow EE (2002) Thalamocortical optimiza- ence of  allodynia. However this study was performed tion of tactile processing according to behavioral state. Nat Neu- rosci 5:517–523 in anaesthetized animals, raising the question of its 13. Radhakrishnan V, Tsoukatos J, Davis KD et al. (1999) A com- applicability to awake thalamic processing. By the parison of the burst activity of lateral thalamic neurons in chronic same token, Radhakrishnan et al. (1999) showed that pain and non-pain patients. Pain 80:567–575 the incidence of thalamic bursting was similar between 14. Sherman SE, Luo L, Dostrovsky JO (1997) Altered receptive fields and sensory modalities of rat VPL thalamic neurons painful and non-painful neurological injuries. Hence, during spinal strychnine-induced allodynia. J Neurophysiol the role of the internal oscillatory states of the thalamus 78:2296–2308 in pain processing is still to be clarified. 15. Weng HR, Lee JI, Lenz FA et al. (2000) Functional plasticity in primate somatosensory thalamus following chronic lesion of References the ventral lateral spinal cord. Neuroscience 101:393–401 1. Albe-Fessard D, Berkley KJ, Kruger L et al. (1985) Diencephalic mechanisms of pain sensation. Brain Res 356:217–296 2. Apkarian AV, Shi T, Brueggemann J et al. (2000) Segregation of nociceptive and non-nociceptive networks in the squirrel monkey Thalamus Lesion somatosensory thalamus. J Neurophysiol 84:484–494 3. Brueggemann J, Galhardo V, Apkarian AV (2001) Immediate  reorganization of the rat somatosensory thalamus following pe- Lateral Thalamic Lesions, Pain Behavior in Animals ripheral partial nerve ligation. J Pain 2:220–228 4. Davis KD, Kiss ZHT, Tasker RR et al. (1996) Thalamic stimulation-evoked sensations in chronic pain patients and non-pain (movement disorder) patients. J Neurophysiol Thalamus, Metabotropic Glutamate 75:1026–1037 5. Gerke M, Duggan A, Xu L et al. (2003) Thalamic neuronal activ- Receptors ity in rats with mechanical allodynia following contusive spinal cord injury. Neuroscience 117:715–722  6. Guilbaud G, Benoist JM, Jazat F et al. (1990) Neuronal re- Metabotropic Glutamate Receptors in the Thalamus sponsiveness in the ventrobasal thalamic complex of rats with an experimental peripheral mononeuropathy. J Neurophysiol 64:1537–1554 7. Katz DB, Simon SA, Moody A et al. (1999) Simultaneous reorga- Thalamus, Nociceptive Cells in VPI, Cat nization in thalamocortical ensembles evolves over several hours after perioral capsaicin injections. J.Neurophysiol 82:963–977 and Rat 8. Lenz FA, Kwan HC, Dostrovsky JO et al. (1989) Characteris- tics of the bursting pattern of action potentials that occurs in the CHRISTIANE VAHLE-HINZ thalamus of patients with central pain. Brain Res 496:357–360 Institute of Neurophysiology and Pathophysiology, 9. Lenz FA, Gracely RH, Baker FH et al. (1998) Reorganization University Hospital Hamburg-Eppendorf, Hamburg, of sensory modalities evoked by microstimulation in region of the thalamic principal sensory nucleus in patients with pain due Germany to nervous system injury. J Comp Neurol 399:125–138 [email protected] 10. Llinas RR, Ribary U, Jeanmonod D et al. (1999) Thalamocorti- cal dysrhythmia: A neurological and neuropsychiatric syndrome characterized by magnetoencephalography. Proc Natl Acad Sci Synonyms USA 96:15222–15227 High-threshold neurons; nociceptive-specific neurons 11. Nicolelis MAL (1997) Dynamic and distributed somatosensory representations as the substrate for cortical and subcortical plas- (NS); wide-dynamic range (WDR) neurons; multire- ticity. Semin Neurosci 9:24–33 ceptive neurons (MR) Thalamus, Nociceptive Cells in VPI, Cat and Rat 2447

Definition  medial part of the posterior complex (POm). Since  Neurons of the lateral thalamus encoding stimulus qual- these have similar receptive field (RF) and response ity, duration, intensity and location on the body and thus properties, it appears that these regions in the lateral subserving the  sensory-discriminative component of thalamus of rats and cats are involved in processing pain. and transmission of nociceptive signals in a similar The neurons respond with an increase or decrease way. of discharge activity to noxious stimuli exclusively ( nociceptive-specific neurons, NS) or with a higher Characteristics discharge to noxious mechanical than to innocuous Nociceptive neurons in the VPp have a less precise so- mechanical stimuli ( wide-dynamic range (WDR) matotopic organization than neurons of the VP proper, neurons) or to both noxious and innocuous mechanical largely due to numerous neurons with larger and com- as well as thermal stimuli (multireceptive neurons). plex RFs consisting of discontinuous areas on the body As defined in “Thalamic Nuclei Involved in Pain, cat surface. However, a coarse mediolateral sequence of and rat” the region termed  ventral posterior inferior head, forelimb and hind limb  RFs is present, running nucleus (VPI) in monkeys may correspond to the small parallel to that of the VP proper, thus forming a second celled region of the ventral periphery of the ventral pos- representation of the body. Due to a lower ongoing terior medial nucleus (VPMvp) in cats, the extensions activity and a sparser packing of neurons, even low of which surround the ventral, lateral and dorsal periph- impedance electrodes hardly pick up any background ery of the  ventral posterior complex (VP).Inrats, activity in contrast to the noisy “hash” characteristic of nociceptive neurons are also found within and around the VP (Kniffki and Vahle-Hinz 1987; Vahle-Hinz et the VP, but most are concentrated in the adjoining al. 1987).

T

Thalamus, Nociceptive Cells in VPI, Cat and Rat, Figure 1 Response characteristics of nociceptive neurons of the cat’s VPp (a,b,c)andtherat’s POm (d). (a) Spike record of a heat-evoked response. The elevated activity representing stimulus duration is followed by a lower afterdischarge for about 30 s before return to prestimulus activity. (b) Multireceptive neuron responding to noxious pressure and heat stimuli in different parts of the receptive field. (c) Wide-dynamic range neuron with graded responses to innocuous pressure and two intensities of noxious pressure. (d) The response elicited by a radiant heat stimulus is abolished by an increase of isoflurane concentration from 0.9% to 1.2%. Spike histograms, bin width 1 s; the bar below each histogram represents the duration of the stimulus (modified from Vahle-Hinz et al. 1987 (a); 2002 (d); Kniffki and Vahle-Hinz 1987 (c)). 2448 Thalamus, Nociceptive Cells in VPI, Cat and Rat

Thalamus, Nociceptive Cells in VPI, Cat and Rat, Figure 2 Excitatory responses of a PO neuron (a) and inhibitory responses of a VPp neuron (b) to noxious distension of the bladder. Peristimulus-time histograms (bin width 1 s) and intravesical pressure (lower traces), with baseline and peak values indicated, are shown on the left. The low-threshold cutaneous RFs of the respective neuron (b, black area) or of the background activity (a, stippled area) are delineated in the figurines. The locations of the recording sites are shown in the line drawings made from the histological sections. (Modified from Brüggemann et al. 1993).

In both cats and rats, the neurons respond to graded the thalamusof both ratsandcats. Some of the additional noxious mechanical and/or heat stimuli (for review somatic RFs of viscero-somatic convergent neurons in see Willis 1997). Responses to noxious heat stimuli the rat are nociceptive (Berkley et al. 1993), while in characteristically occur after long latencies (several the cat most are of the low-threshold type. The major- seconds), which may result from receptor activation ity of these somatic low-threshold RFs are located in ar- time and transmission by C fibers. The discharge in- easincluding dermatomesto which pain isreferred from crease in many neurons encodes stimulus duration, the respective visceral organs (Brüggemann et al. 1993; often followed by a lower but still increased afterdis- Horn et al. 1999; Vahle-Hinz et al. 1995). charge for several tens of seconds (Fig. 1a, b, d). A The neuronal responses in the lateral thalamus indicate threshold temperature and a stimulus-response func- that distinct response properties are segregated (e.g. so- tion resembling psychophysical heat pain in humans matic and visceralnociceptive-specific), thusincreasing are found. All types of nociceptive neurons are present, the diversity of response characteristics contained in nociceptive-specific (Fig. 1a, d), multireceptive (Fig. the population of nociceptive neurons. Excitatory and 1b) and WDR neurons (Fig. 1c). NS and WDR/MR inhibitory interactions between inputs from different neurons occur in about equal proportions in the cat, somatic sources (mechanoreceptive/nociceptive) or while the majority in the rat is of the NS-type. Thalamic visceral organs may help to focus the activity and hence nociceptive neurons are sensitive to anesthetics; the the sensation to a certain stimulus or organ. response to a noxious stimulus may be abolished by a slight increase of anesthetic dose without a marked References suppression of the neuron’s ongoing discharge activity 1. Brüggemann J, Vahle-Hinz C, Kniffki K-D (1993) Representa- (Fig. 1d). Different classes of anesthetic agents appear tion of the urinary bladder in the lateral thalamus of the cat. J to block nociceptive signal transmission at different Neurophysiol 70:482–491 subthalamic/thalamic sites within the ascending path- 2. Berkley KJ, Guilbaud G, Benoist J-M et al. (1993) Responses of neurons in and near the thalamic ventrobasal complex of the rat ways. The low-threshold mechanoreceptive responses to stimulation of uterus, vagina, colon, and skin. J Neurophysiol in contrast are more robust (Vahle-Hinz and Detsch 69:557–568 2002; Vahle-Hinz et al. 2002). 3. Horn AC, Vahle-HinzC, Brüggemann J et al. (1999) Responses of As with noxious somatic stimuli and also with visceral neurons in the lateral thalamus of the cat to stimulation of urinary bladder, colon, esophagus, and skin. Brain Res 851:164–174 stimulation, both excitation and inhibition of thalamic 4. Kniffki K-D, Vahle-Hinz C (1987) The periphery of the cat’s neuronal discharges can be elicited (Fig. 2). In contrast ventroposteromedial nucleus (VPMp ): Nociceptive neurones. In: to the spinal cord level, where the majority of viscero- Besson J-M, Guilbaud G, Peschanski M (eds) Thalamus and Pain. ceptive neurons have convergent somatic inputs of the Elsevier, Amsterdam, pp 245–257 5. Vahle-Hinz C, Brüggemann J, Kniffki K-D (1995) Thalamic pro- WDR type, visceroceptive-specific neurons are found in cessing of visceral pain. In: Bromm B, Desmedt J (eds) Pain and Thalamus, Nociceptive Inputs in the Rat (Spinal) 2449

the Brain. From Nociception to Cognition. Advances in Pain Re- regions of the dorsal horn, the superficial and the deep serach and Therapy, vol 22. Raven Press, New York, pp 125–141 laminae, have key roles in the processing of nociceptive 6. Vahle-Hinz C, Detsch O (2002) What can in vivo electrophysi- ology in animal models tell us about mechanisms of anesthesia? messages. Br J Anaesth 89:123–142 Thesuperficiallaminae(I and II) haveamajor rolein no- 7. Vahle-Hinz C, Freund I, Kniffki K-D (1987) Nociceptive neurons ciceptive processing because this region is the main re- in the ventral periphery of the cat thalamic ventroposteromedial cipientfor peripheralnociceptiveinputsconveyedbyAδ nucleus. In: Schmidt RF, Schaible H-G, Vahle-Hinz C (eds) Fine Afferent Nerve Fibers and Pain. VCH Verlagsgesellschaft, Wein- and C fibers. Whereas both the laminae I and II receive heim, pp 440–450 nociceptive inputs, only the lamina I neurons project to 8. Vahle-Hinz C, Reeker W, Detsch O et al (2002) Antinociceptive supraspinal centers. These neurons are the main output effects of anesthetics in vivo : Neuronal responses and cellular of this superficial region. The lamina I neurons are pri- mechanisms. In: Urban BW, Barann M (eds) Molecular and Ba- sic Mechanisms of Anesthesia. Pabst Sci Publ, Lengerich, pp marilynociceptive,amajorityofthembeingnociceptive 516–524 specific(ChristensenandPerl1970).Inaddition,alower 9. Willis WD (1997) Nociceptive functions of thalamic neurons. proportion of lamina I neurons can encode specifically In: Steriade M, Jones EG, McCormick DA (eds). Thalamus, Vol. innocuous thermal stimuli (Light et al. 1993). II, Experimental and Clinical Aspects. Elsevier, Amsterdam, pp 373–424 The second area of the dorsal horn, which processes nociceptive messages, includes the deep laminae V, VI and the adjacent portion of the lamina VII. The involve- Thalamus, Nociceptive Inputs in the Rat ment of deep laminae in nociceptive processing was chiefly demonstrated by electrophysiology; this region (Spinal) contains numerous wide dynamic range neurons that JEAN-FRANÇOIS BERNARD have a great ability to encode noxious stimuli but from Institut National de la Santé et de la Recherche a clearly innocuous range (Besson and Chaouch 1987). Médicale, INSERM U-677, Paris, France The anatomical link of this region with peripheral Aδ [email protected] and C nociceptive fibers is less clear; deep laminae neurons receive some collateral projections from Aδ Definition and C fibers, but the main nociceptive input might be conveyed indirectly via superficial laminae. Layers of the Spinal Cord The caudal thalamus is a primary brain center for pain Thegray matter of thespinalcord isdivided, from dorsal processing. Nociceptive information is conveyed to to ventral, into 10 laminae on the basis of cytoarchitec- the thalamus from nociceptive neurons in lamina I tonic criteria. The dorsal horn includes the laminae I to and deep laminae of the spinal cord 1) directly via the VI; the lamina VII is an intermediate area; the ventral spino-thalamic tract and 2) indirectly via relay nuclei horn includes the laminae VIII and IX (motoneurons); in the brainstem. the region around the central canal corresponds to the lamina X. Spinal Nociceptive Inputs to the Thalamus Thalamus Retrograde tracing studies show that neurons projecting to the thalamus are located in lamina I and in deep lam- T The caudal portion of the thalamus is an important brain inae of the spinal cord (Burstein et al. 1990). Thalamic center for somatosensory and nociceptive processing. projecting superficial spinal neurons are clearly con- This caudal region is often divided into the lateral and centrated in lamina I of the dorsal horn, only very few the medial thalamus. 1) The lateral thalamus is primar- are located in lamina II. Lamina I neurons are evenly ily a relay that includes chiefly, for somatosensory func- distributed along the spinal cord, with higher concentra- tions, the ventral posterolateral (VPL), the ventral pos- tions at the levels of cervical and lumbar enlargements. teromedial (VPM), the posterior group (Po) and the tri- On the other hand, thalamic projecting deep laminae angular posterior group (PoT) thalamic nuclei. 2) The neurons are scattered in deep laminae of the spinal cord medial thalamus might be regarded as a more integra- (III to VIII and X) although they are more numerous tive region that includes intralaminar [chiefly the cen- around the laminae IV – VI. These thalamic projecting tral lateral (CL), paracentral (PC), central medial (CM) deep laminae neurons are not evenly distributed in the and parafascicular (Pf) nuclei], paralaminar [notablythe spinal cord, since almost half of them are concentrated ventral medial (VM) nucleus] and median thalamic nu- in the two first spinal segments (C1, 2). In the cervical clei. enlargement (C5 – 8), which relays nociceptive mes- Characteristics sages from the forelimb, one spino-thalamic neuron in lamina I and one in the deep lamina were counted on The Spinal Relay average per 50 μm section (Burstein et al. 1990). Noxious messages are conveyed from the periphery Anterograde tracing studies, using a high-resolution (trunk and limbs) to the thalamus via a primary relay, tracer such as the Phaseolus vulgaris leucoagglutinin the dorsal horn of the spinal cord. Two individualized (PHA-L), allowed the demonstration of separate pro- 2450 Thalamus, Nociceptive Inputs in the Rat (Spinal)

Thalamus, Nociceptive Inputs in the Rat (Spinal), Figure 1 Summary diagram of spinal projections to the thalamus. (a1) Lamina I (hatching) projecting area in the cervical enlargement of the spinal cord. (b1) Projection in the PoT (hatching) from lamina I. (c1) Projection to VPL, Po and VPPC thalamic nuclei (hatching) from lamina I. (a2) Deep laminae (black points) and SL nucleus (gray) projecting area in the cervical enlargement. (b2) Projection to PoT thalamic nucleus (points) from the deep laminae. (c2) Projection to CL (points) and MD (gray) thalamic nuclei from deep laminae and SL nucleus, respectively. Scale bars = 1 mm. Abbreviations: I-X, laminae I-X of the spinal cord; APT, anterior pretectal nucleus; CL, central lateral thalamic nucleus; CM, central medial thalamic nucleus; DMH, dorsomedial hypothalamic nucleus; eml, external medullary lamina; f, fornix; LHp, lateral hypothalamus posterior; MD, mediodorsal nucleus; MG, medial geniculate nucleus; ml, medial lemniscus; mt, mammillothalamic tract; PAG, periaqueductal gray matter; PC, paracentral thalamic nucleus; PH, posterior hypothalamus; PIL, posterior intralaminar thalamic nucleus; Po, posterior thalamic group; PoT, posterior thalamic group, triangular part; Re, reuniens nucleus; SL, spinal lateral nucleus; SN, substantia nigra; VM, ventromedial thalamic nucleus; VMH, ventromedial hypothalamic nucleus; VPL, ventral posterolateral thalamic nucleus; VPM, ventral posteromedial thalamic nucleus; VPPC, ventral posterior parvocellular thalamic nucleus; ZI, zona incerta. jections from lamina I and deeplaminae of the spinal axonal endingshave large varicosities (Fig. 2). Other cord upon the thalamus (Gauriau and Bernard 2003). substantial projections with small varicosities were ob- The projections from lamina I are markedly different served in the PoT and the ventral posterior parvocellular from those of deep laminae (Fig. 1). nucleus(VPPC).Onlyamoderatenumberofprojections Lamina I neuronsprojectprimarily torestricted portions are observed in a few additional thalamic targets such as of the VPL and rostral Po (Fig. 1a1–c1). In these areas, the periventricular, the subparafascicular, the reuniens Thalamus, Nociceptive Inputs in the Rat (Spinal) 2451

A last notable projection is from the spinal lateral neu- rons to the caudal portion of the mediodorsal nucleus (Fig.1 a2–c2).

Brainstem Nociceptive Inputs to the Thalamus Thespino-thalamictractisoftenconsideredtobethepri- marypathwayconveyingnociceptivemessagesfromthe spinal cord to the thalamus. In fact, the number of spino- thalamic neurons (9500 is the higher estimation in the rat;Bursteinetal.1990)issubstantialbutrepresentsonly a very small proportionof dorsal horn neurons. Further- more,anterogradestudiesinprimate(Mehleretal.1960) as well as in the rat (Gauriau and Bernard 2003) indicate that spinal projections are clearly more extensive upon the brainstem than to the thalamus. These data strongly suggest that the brainstem should have an important role in conveying nociceptive input from the spinal cord to the thalamus and the other brain centers. The gigantocellular reticular (Gi) nucleus, located in the centerofthemedulla,wasthefirstcandidatetofulfillthis role (Casey 1971; Bowsher 1976). This nucleus receives an extensive projection from deep laminae of the spinal cord, it contains numerous nociceptive neurons and its stimulation produces aversive reactions. However, the portion of the Gi that receives the densest spinal pro- Thalamus, Nociceptive Inputs in the Rat (Spinal), jection projects primarily to the locus coeruleus and the Figure 2 Photomicrographs of the projection from lamina I to the thalamus. (a) PHA-L injection site in laminae I/II of the cervical spinal cord and only weakly to the thalamus. enlargement. (b) Extensive terminal labeling with large varicosities in the The subnucleus reticularis dorsalis (SRD), a very caudal VPL thalamic nucleus resulting from the injection in (a). Scale bars = reticular area of the medulla, located just ventral to the 500 μm in A, 100 μm in (b). Abbreviations: I-X, laminae I-X of the spinal cuneate nucleus, now appears to be the best candidate to cord; VPL, ventral posterolateral thalamic nucleus. convey nociceptive messages from the spinal cord to the thalamus. Indeed, the SRD receives an extensive projec- tion from deep laminae of the spinal cord (Raboisson et al. 1996). Electrophysiological studies demonstrate the and the mediodorsal nuclei; no projection is observed involvement of this reticular region in nociceptive pro- to the submedius nucleus. Lamina I projections to the cessing. Indeed, most of the SRD neurons are strongly thalamus are almost exclusively contralateral. Because excitedbynoxiousstimulifromalowspontaneousactiv- T the VPL/Po system is also known to be the thalamic ity and do not respond to multisensory (visual and audi- relay conveying somatotopically tactile messages from tory) stimuli. SRD neurons encode the intensity of ther- gracile and cuneate nuclei to somatosensory SI and SII mal, mechanical and visceral noxious stimuli. They re- cortex, it appears likely that the lamina I – VPL/Po sys- spond exclusively to the activation of peripheral Aδ-or tem is devoted to somatosensory discriminative aspects Aδ- and C-fibers. Such responses are depressed by in- of nociception. The role of the lamina I – PoT/VPPC travenous morphine in a dose-dependent and naloxone- systemislessclear,itcouldparticipatetotherecognition reversiblefashion(Villanuevaetal.1996).Thereceptive of the “painful” nature of nociceptive stimuli. fields of SRD neurons are very large; they often include Deep laminae neurons project chiefly to the central lat- the whole body. The main thalamic targets of the SRD eral intralaminar and the PoT thalamic nuclei on both arethelateralportionsoftheVMnucleus,(Fig.3)and,to sides (Fig.1 a2–c2). Very few projections are observed a lesser extent, of the Pf nucleus (Villanueva et al. 1998). to other thalamic nuclei. In fact, itappears that deep lam- The internal lateral parabrachial (PBil) nucleus, located inae neurons project as much to the thalamus as to ex- in a dorsalposition atthe ponto-mesencephalicjunction, trathalamic targets, such as the substantia innominata, isanothercandidateforconveyingnociceptivemessages the globus pallidus, the posterior and lateral hypothala- from the spinal cord to the thalamus. The PBil should mus and the central amygdaloid nucleus. These recent not be mixed up with the lateral parabrachial area, which findings clearly question the projections of deep lami- receives an extensive projection from lamina I and does nae to the VPL, suggesting strongly that the main noci- not project substantially to the thalamus. In fact, the PBil ceptive inputs to the VPL originate primarily from the specifically receives a dense projection from deep lami- lamina I neurons, in the rat. nae of the spinal cord (especially from the reticular por- 2452 Thalamus, Nociceptive Inputs in the Rat (Spinal)

Thalamus, Nociceptive Inputs in the Rat (Spinal), Figure 3 Photomicrographs of the projection from the SRD to the thalamus. (a) PHA-L injection site in the SRD. (b) High density of labeled terminals in the lateral portion of the VM. (c) Higher magnification of the labeled terminals in the region delineated in (b). Note the numerous terminals with small varicosities. Scale bars = 500 μm in (a), (b), 100 μm in (c). Abbreviations: Cu, cuneate nucleus; SRD, subnucleus reticularis dorsalis; VM, ventromedial thalamic nucleus; VPL, ventral posterolateral thalamic nucleus; VPM, ventral posteromedial thalamic nucleus.

Thalamus, Nociceptive Inputs in the Rat (Spinal), Figure 4 Photomicrographs of the projection from the PBil to the thalamus. Note the high density of labeled terminals concentrated in the PC (black area on both sides) with a lower density of labeling in the CM (a) resulting from the PHA-L injection covering the PBil (b). Scale bars = 500 μm. Abbreviations: 3V, third ventricle; bc, brachium conjunctivum; CL, central lateral thalamic nucleus; CM, central medial thalamic nucleus; iml, internal medullary lamina; MD, mediodorsal thalamic nucleus; OPC, oval paracentral thalamic nucleus; PBil, internal lateral parabrachial nucleus; PC, paracentral thalamic nucleus; Rh, rhomboid thalamic nucleus. tion of laminae IV and V) (Bernard et al. 1995). The spino-thalamic tract. Indeed, deep laminae neurons PBil neurons project primarily to the PC thalamic nu- send nociceptive messages to the medial thalamus di- cleus (Fig. 4) and, to a lesser extent, to the CM and the Pf rectly via the spino-thalamic tract, as well as indirectly thalamic nuclei (Bester et al. 1999). Electrophysiologi- via SRD and PBil neurons. Thus this system could deal calstudiesdemonstratetheinvolvementofthalamicpro- with alertness and emotional and motor aspects of pain jecting PBil neurons in nociceptive processing. Indeed, through a general arousal of the prefrontal and frontal most of them respond to thermal and noxious stimuli, (motor) cortices (the cortical targets of the medial with a maximum response in the mid-nociceptive scale thalamus). (48˚C and 16 N/cm2). The PBil neurons exhibit strong “wind up” and long lasting after-discharge in response Synthesis to noxious stimuli (Bourgeais et al. 2001). Nociceptive inputs to the thalamus can be classified in With regard to the deep laminae system, the brainstem the two different systems summarized in Fig. 5 as fol- clearly has an important complementary role to the lows: Thalamus, Nociceptive Inputs in the Rat (Spinal) 2453

Thalamus, Nociceptive Inputs in the Rat (Spinal), Figure 5 Schematic representation of the main nociceptive inputs to the thalamus, in the rat. Red: Main inputs to the lateral thalamus from the lamina I of the spinal cord. Blue: Main inputs to the medial thalamus originating from the deep laminae of the spinal cord, directly via the spino-thalamic tract, and indirectly via the SRD and the PBil nuclei. Abbreviations: I-X, laminae I-X of the spinal cord; APT, anterior pretectal nucleus; ar, acoustic radiation; bc, brachium conjunctivum; BL, basolateral amygdaloid nucleus; Ce, central amygdaloid nucleus; CL, central lateral thalamic nucleus; CM, central medial thalamic nucleus; CPu, caudate putamen (striatum); Cu, cuneate nucleus; DMH, dorsomedial hypothalamic nucleus; Eth, ethmoid thalamic nucleus; f, fornix; Gr, gracilis nucleus; ic, internal capsule; IO, inferior olive; La, lateral amygdaloid nucleus; LC, locus coeruleus; LRt, lateral reticular nucleus; Me, medial amygdaloid nucleus; MG, medial geniculate nucleus; ml, medial lemniscus; mt, mammillothalamic tract; opt, optic tract; PBil, internal lateral parabrachial nucleus; PBl, lateral parabrachial nucleus; PBm, medial parabrachial nucleus; PC, paracentral thalamic nucleus; PIL, posterior intralaminar thalamic nucleus; Po, posterior thalamic group; PoT, posterior thalamic group, triangular part; pyx, pyramidal decussation; SG, suprageniculate thalamic nucleus; Sol, solitary tract nucleus; Sp5C, spinal trigeminal nucleus caudal part; SPF, subparafascicular nucleus; SRD, T subnucleus reticularis dorsalis; VL, ventrolateral thalamic nucleus; VM, ventromedial thalamic nucleus; VMH, ventromedial hypothalamic nucleus; VPL, ventral posterolateral thalamic nucleus; VPM, ventral posteromedial thalamic nucleus.

eral/ventrolateral quadrant in the rat. Thus, it appears 1. The lamina I – (lateral) thalamic system, which clear that the strikingly acute effectiveness of ventrolat- could be chiefly responsible for sensory discrimina- eral cordotomy is due to the interruption of both a direct tion of nociceptive stimuli via thalamic projections spino-thalamic tract and a strong spino-brainstem- to somatosensory cortices (SI, SII, Insular). thalamic pathway. 2. The deep laminae – (medial) thalamic system, which An additional nociceptive pathway to the thalamus (not includes two subsystems: a direct deep laminae – me- illustrated)wasproposedbythegroupofWillis.Thevis- dial thalamic pathway and an indirect deep laminae ceral (colorectal) nociceptive information, after a relay – SRD/PBil – medial thalamic pathway. This system in laminae X and VII of the lumbo-sacral spinal cord, couldbeinvolvedinmotorandalertness/arousalemo- would be conveyed via the medial portion of the dorsal tional features of pain via the medial thalamic projec- column and the gracile nucleus to the VPL thalamic nu- tions to the frontal motor and the prefrontal medial cleus.Thekeypointinthedemonstrationofthispathway (cingulate) cortices. is the strong effect of a medial commissurotomy (in the The spinal ascending axons of all these systems are middle of dorsal column fasciculus) upon the response located around the same region of the spinal lat- of VPL neurons to visceral noxious stimuli and visceral 2454 Thalamus, Nociceptive Neurotransmission pain (Willis et al. 1999). However, the existence of such a pathway remains difficult to reconcile with previous Thalamus, Receptive Fields, Projected clinical and experimental data. Fields, Human

NIRIT WEISS,SHINJI OHARA,STAN ANDERSON, References FRED A. LENZ 1. Bernard JF, Dallel R, Raboisson P et al. (1995) Organization of Departments of Neurosurgery, Johns Hopkins the efferent projections from the spinal cervical enlargement to University, Baltimore, MD, USA the parabrachial area and periaqueductal gray: a PHA-L study fl[email protected] in the rat. J Comp Neurol 353:480–505 2. Besson JM, Chaouch A (1987) Peripheral and spinal mechanisms of nociception. Physiol Rev 67:67–186 Synonyms 3. Bester H, Bourgeais L, Villanueva L et al. (1999) Differential Thalamic Physiology Changes Occurring in Patients projections to the intralaminar and gustatory thalamus from the parabrachial area: A PHA-L study in the rat. J Comp Neurol with Chronic Pain 405:421–449 4. Bourgeais L, Monconduit L, Villanueva L et al. (2001) Definition Parabrachial internal lateral neurons convey nociceptive mes- sages from the deep laminas of the dorsal horn to the intralaminar Physiologic changes in the thalamus seen in patients thalamus. J Neurosci 21:2159–2165 with chronic pain syndromes. These changes are re- 5. Bowsher D (1976) Role of the reticular formation in responses flected in alterations in the properties of neurons and to noxious stimulation. Pain 2:361–378 assemblies of neurons in patients who suffer from 6. Burstein R, Dado RJ, Giesler GJ Jr (1990) The cells of origin of the spinothalamic tract of the rat: a quantitative reexamination. chronic pain. Brain Res 511:329–337 7. Casey KL (1971) Somatosensory responses of bulboreticular Characteristics units in awake cat: relation to escape-producing stimuli. Science  173:77–80 Studies of the plasticity of the somatosensory system 8. Christensen BN, Perl ER (1970) Spinal neurons specifically ex- in non-human primateshave focused on mapsof cortical cited by noxious or thermal stimuli: marginal zone of the dorsal function determined by examining neuronal  receptive horn. J Neurophysiol 33:293–307 fields (RFs) (Kaas 1991). Studies in humans can explore 9. Gauriau C, Bernard JF (2003) A comparative reappraisal of pro- jections from the superficial laminae of the dorsal horn in the both maps determined from RFs (RF maps) and maps of rat: the forebrain. J Comp Neurol 468:24–56 the locations and quality of sensations evoked by stimu- 10. Light AR, Sedivec MJ, Casale EJ et al. (1993) Physiological lationofthebrain( projectedfieldorPFmaps)(Lenzet and morphological characteristics of spinal neurons projecting al.1994).WhileRFmapsareareflectionoftheorganiza- totheparabrachial region ofthe cat. SomatosensMot Res10:309–  325 tion of inputs to the central nervous system, PF maps 11. Mehler WR, Feferman ME, Nauta W (1960) Ascending axon de- give an indication of the image of the body contained in generation following anterolateral cordotomy. An experimental the thalamus and cortex. There are numerous studies of study in the monkey. Brain 83:718–751 cortical plasticity secondary to injuries of the nervous 12. Raboisson P, Dallel R, Bernard JF et al. (1996) Organization of efferent projections from the spinal cervical enlargement to system (Kaas 1991). Although much of the reorganiza- the medullary subnucleus reticularis dorsalis and the adjacent tion of cortical maps may reflect underlying changes in cuneate nucleus: a PHA-L study in the rat. J Comp Neurol thalamic organization (Pons et al. 1991), there are rela- 367:503–517 tively few direct studies of thalamic plasticity (Rasmus- 13. Villanueva L, Bouhassira D, Le Bars D (1996) The medullary subnucleus reticularis dorsalis (SRD) as a key link in both son 1996). the transmission and modulation of pain signals. Pain 67:231– Medically intractable chronic pain due to nervous sys- 240 tem injury or medically intractable movement disorders 14. Villanueva L, Desbois C, Le Bars D et al. (1998) Organiza- tion of diencephalic projections from the medullary subnucleus may be surgically treated by implantation of deep brain reticularis dorsalis and the adjacent cuneate nucleus: A retro- stimulatingelectrodesintheprincipalsensorynucleusof grade and anterograde tracer study in the rat. J Comp Neurol the thalamus ( ventral caudal – Vc) (Hosobuchi, 1986) 390:133–160 or by  thalamotomy (Tasker et al. 1988). During such 15. Willis WD, Al-Chaer ED, Quast MJ et al. 1999 A visceral pain pathway in the dorsal column of the spinal cord. Proc Natl Acad operations, microelectrode recordings may be used to Sci USA 96:7675–7679 confirm the target predicted by the radiological studies. The physiological studies of Vc in patients with chronic pain syndromes are compared with the recordings of Vc in patients with movement disorders and thus plasticity of pain-related neuronal activity in the human thalamus can be studied directly. Thalamus, Nociceptive The region of the principal sensory nucleus of thalamus Neurotransmission (Vc) was explored during stereotactic surgical pro- cedures for treatment of patients with pain following spinal cord transection and compared to results from  Nociceptive Neurotransmission in the Thalamus patients with movement disorders (Lenz et al. 1994). Thalamus, Receptive Fields, Projected Fields, Human 2455

Many cells in the expected representation of the anes- of the border of the anesthetic part is increased in mon- thetic part of the body did not have RFs. However, in the keys with nerve sections (Garraghty and Kaas 1991). border zone/anesthetic zone between the anesthetic and Studies have shown that stimulation of the somatic sen- innervated areas of the thalamus, there was frequently sory thalamus is more likely to evoke pain in patients a mismatch between the location of RFs and PFs. Often with chronic pain after nervous system injury than in pa- RFs were located on the chest and abdominal wall, tients without somatic sensory abnormalities (patients above the level of the spinal transection, while PFs with movement disorders) (Lenz et al. 1998). The re- were located in the lower extremity, below the spinal gion of Vc was divided on the basis of projected fields transection. into areas representing the part of the body where the Border zone/anesthetic areas of thalamus often exhib- patients experienced chronic pain (pain affected) or did ited increased representations of the border of the anes- not experience chronic pain (pain unaffected) and into thetic part of the body. Two sites were said to have a con- a control area located in the thalamus of patients with sistentRFiftheRFofbothsitesincludedthesamepartof movement disorders and no experience of chronic pain. thebody.ThelengthofatrajectorywithconsistentRFsis In both the core and posterior inferior regions of the the distance along the trajectory where each RF contin- thalamic sensory nucleus, the proportion of sites where uestoincludethesamepartofthebody(Lenzetal.1988). threshold microstimulation evoked pain was larger in The maximal distance along a trajectory over which the pain affected and unaffected areas than in control areas. RF or the PF stays consistent is longer for body parts Thenumberofsiteswherethermal(warmorcold)sensa- withlargerrepresentations(Lenzetal.1994).Lengthsof tions were evoked was correspondingly smaller, so that trajectory with a consistent RF in a particular part of the the total of pain plus thermal sites was not significantly body weresignificantly longer inborderzone/anesthetic different across all areas (Lenz et al. 1998). Therefore, zonesthanincontrolareaswithapparentlynormalinput. sites where stimulation evoked pain in patients with Neurons with RFs adjacent to the area of sensory loss neuropathic pain may correspond to sites where ther- in amputation patients (n=3) occupied a larger part of mal sensations were evoked by stimulation in patients the thalamic homunculus (Lenz et al. 1998) than found without somatic sensory abnormality. In the posterior for the same part of the body in patients with movement inferior region, the number of sites where cold was disorders (Lenz et al. 1988; Lenz et al. 1994). This result evoked by stimulation decreased significantly, while is consistent with somatotopic reorganization of affer- the number of sites where pain was evoked increased ent inputs from the limb. Similarly the large area over significantly. which PFs include the stump (Lenz et al. 1994; Lenz et These results suggest that pain is evoked in patients al. 1993)) suggest that there has been reorganization of with neuropathic pain by stimulation at sites where the perceptual image of the limb in the central nervous thermal sensations would normally be evoked. There- system (Jensen and Rasmussen 1994). It has also been fore, the present data suggest that the STT, or elements reported thatphantom sensationscan beevoked bystim- to which the STT projects, signal pain rather than ther- ulation of the region where stump RFs are located in the mal sensations in patients with neuropathicpain. This is region of Vc (Davis et al. 1998). Thus, in the case of consistent with the finding that stimulation of the STT amputations and spinal cord injury, the alteration in the evokes pain in patients with neuropathic pain but evokes T image of the body in the thalamus is less than that of the nonpainful thermal sensations in patients who do not inputs from that part of the body. have neuropathic pain (Tasker 1988). Cordotomy re- In primates there are well-documented alterations in lieves pain in a much greater proportion of patients with thalamic anatomy and physiology after peripheral nerve somatic pain than it does in patients with neuropathic injury. The distributions of thalamic regions with char- pain (Sweet et al. 1994). The failure of cordotomy to acteristic histology are altered (Rausell et al. 1992) relieve neuropathic pain might be anticipated from the in monkeys with a C2-T4 dorsal rhizotomy (Sweet occurrence of central pain in patients with impaired 1981). In the affected arm area of rhizotomized ani- function of the STT (Cassinari and Pagni 1969; Boivie mals, there is a reduction in the density of large cells and et al. 1989). These results suggest that the generator for of  parvalbumin and  CO staining, all characteristic pain in patients with central pain is the terminus of the of the terminal zone for dorsal column inputs. There is STT. a corresponding increase in the  calbindin staining in In patients with central pain, anatomic evidence of the arm area, characteristic of the terminal zone for STT damage to STT is a common finding (Cassinari and inputs. Pagni 1969) and loss of STT function, indicated by After cervical dorsal rhizotomy, large numbers of cells impaired thermal and pain sensibility, is a uniform without RFs are encountered (Albe-Fessard and Lom- finding (Boivie 1994). In patients with central pain, bard 1983) in theforelimb regionof themonkey VP.Fol- pain is more common than in controls, while threshold lowing adult digit amputation, increased representation microstimulation-evoked cold sensations are corre- of the stump is found, with large RFs including adjacent spondingly less common. These findings suggest that digits (Rasmusson 1996). The thalamic representation there has been a reorganization, so that cold modalities 2456 Thalamus, Receptive Fields, Projected Fields, Human are relabeled to signal pain in the thalamus of patients 4. Cassinari V, Pagni CA (1969) Central Pain. A neurosurgical sur- with central pain (Ralston et al. 1996). The relationship vey. Harvard University Press, Cambridge, Massachusetts 5. 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These results sug- neurons in the ventroposterior lateral thalamic nucleus of the rac- gest that the perceptual representation of the body in the coon after peripheral deafferentation. J Neurophysiol 75:2441– 2450 thalamus reorganizes less than the representation of in- 20. Rausell E, Cusick CG, Taub E et al. (1992) Chronic Deaf- puts to the thalamus. Although the central image of the ferentation in monkeys differentially affects nociceptive and body is relatively constant in the face of altered input, non-nociceptive pathway distinguished by specific calcium- our studies show that changes in the modality organi- binding protiens and down-regulates gamma-aminobutyric acid type A receptors at thalamic levels. Proc Natl Acad Sci USA zation of this image can change dramatically (Lenz et 89:2571–2575 al. 1998). This plasticity of modality organization may 21. Sweet WH (1981) Animal models of chronic pain: their possible contribute to the development of chronic pain in patients validation from human experience with posterior rhizotomy and with nervous system injury. congenital analgesia. Pain 10:275–295 22. Sweet WH, Poletti CE, Gybels GM (1994) Operations in the References brainstem and spinal canal with an appendix on the relationship of open and percutaneous cordotomy. In: Wall PD, Melzack R 1. Albe-Fessard DG, Lombard MC (1983) Use of an animal model (eds) Textbook of Pain. Churchill and Livingston, New York, pp to evaluate the origin of and protection against deafferentation 1113–1136 pain. Adv Pain ResTher 5:691–700 23. Tasker RR (1988) Percutaneous Cordotomy: The Lateral High 2. Boivie J (1994) Central pain. In: Wall PD, Melzack R (eds) Text- Cervical Technique. In: Schmidek HH, Sweet WH (eds) Oper- book of Pain. Churchill Livingston, Edinburgh, pp 871–902 ative Neurosurgical Techniques Indications, Methods, and Re- 3. Boivie J, Leijon G, Johansson I (1989) Central post-stroke pain sults. Saunders WB, Philadelphia, pp 1191–1205 – a study of the mechanisms through analyses of the sensory 24. Tasker RR, Doorly T, Yamashiro K (1988) Thalamotomy in Gen- abnormalities. Pain 37:173–185 eralized Dystonia. Adv Neurol 50:615–631 Thalamus, Visceral Representation 2457

anesthetized preparations; thus they should be regarded Thalamus, Visceral Representation as examples of responses undoubtedly stunted due to A. VANIA APKARIAN anesthesia. Feinberg School of Medicine, Department of The earliest evidence for visceral inputs to the thala- Physiology, Northwestern University, Chicago, IL, mus and cortex used electrical stimulation of the vagus USA (Bailey and Bremer 1938; Dell and Olson 1951) and [email protected] demonstrated a relay from the lateral thalamus to the  insular cortex from visceral organs. More recent anatomic studies have elucidated that the visceral in- Synonyms puts through vagal afferents terminate in the solitary Interoception; Visceral Modulation; Visceral Represen- tract, second order neurons then project ipsilaterally tation; referred pain to the parabrachial nucleus and third order neurons travel contralaterally to the ventroposterior parvocel- Definition lular nucleus of the thalamus (VPpc) and then project to the insula. A separate projection from parabrachial Stimulation of visceral organs distinctly activates dif- regions directly accesses the insula too, see chapter by ferent populations of neurons in the thalamus. Neurons Cechetto in Gebhart (1995).  Calcitonin gene related located in  parvocellular VP (VPpc) are described as peptide (CGRP) seems to label this pathway in rats as visceral-specific, while neurons located in other medial well as in man. Using a combination of physiological and lateral thalamic nuclei respond to multiple viscera recordings from insular cortex and tracing techniques, and to somatic inputs convergently. Other thalamic nu- it was demonstrated that the most medial portion of clei do not receive visceral inputs. the VPpc projects to the insular region with gustatory responses, while a more lateral portion projects to part Characteristics of the insula with gastric mechanoreceptor responsive In contrast to somatic stimuli, visceral stimuli may or neurons and the most lateral portion projects to an area may not be accompanied by perception and the per- with cardiopulmonary responses; parabrachial inputs ceptions show distinct properties. For example, baro- to the thalamus seem to have a parallel organization as and chemo-receptor activation do not give rise to sen- well (Cechetto and Saper 1987; Gebhart 1995). More sations/perceptions, although they are represented in recent studies in the rat confirm the parabrachial inputs visceral specific portions of the thalamus and in insular and also show inputs from spinal cord and trigemi- cortex. On the other hand, distension of most hollow nal lamina I (Bester et al. 1999; Gauriau and Bernard viscera is associated with ill-defined sensations. Vis- 2004). Thus, the VPpc portion of the thalamus seems ceral nociceptive stimuli in such organs are generally to be viscerotopically organized, where gustatory re- characterized by a sense of malaise or discomfort, with sponses have been shown physiologically (Ganchrow no clear ability to localize the source of the stimu- and Erickson 1972). lus. Moreover, visceral pains are usually associated Inputs from pelvic viscera to the cat lateral thalamus with pain referred on the skin, the location of which have been mapped with electrical stimulation and nat- T is characteristic for different viscera, an association ural stimulation of the urinary bladder (Brüggemann et used since antiquity to pinpoint specific viscera as al. 1993; Brüggemann et al. 1994). Identified neurons the source of injury or inflammation. Thus, the con- were all found located outside the  VPL, either just trast between visceral and somatic representation and in its periphery or in the adjacent  posterior nucleus associated differences in perception provides an op- (PO). All visceral responsive neurons also responded portunity for dissecting conscious perceptions from to low-threshold stimuli applied to the skin. A simi- unconscious modulation, in relationship to thalamocor- lar study examined renal nerve stimulus responses to tical connectivity. Unfortunately very little effort has map kidney representation in and around the  VPL been invested in this direction. It should also be added in the cat (Horn et al. 1997). Most responsive units that visceral stimuli that do not evoke any conscious were located in the periphery of the VPL, dorsal PO or sensations and are represented at the level of the thala- lateral PO; none were found within the VPL. Response mus and cortex, most probably play a modulatory role latency suggested large and small myelinated afferent in emotional responses to the environment and exert fibers mediating kidney inputs. The somatic receptive emotionally driven modulatory control over somatic fields of the cells with renal nerve inputs showed mini- and visceral responses. This notion, however, remains mal correspondence with the dermatomes of the renal mainly a speculation, since direct studies on the topic nerve. A subsequent study mapped the same region of are minimal (Gebhart 1995). Here we concentrate on the thalamus in the cat for bladder, colon and esophagus thalamic neuronal response properties from the view- inputs and again found the majority of cells localized point of coding visceral stimuli and being modulated to either the periphery of the VPL or the  PO and no by visceral stimuli. All the available data are from indication of segregation of neurons based on responses 2458 Thalamus, Visceral Representation

localized within the  mediodorsal (MD),  central medial (CM),  central lateral (CL), periphery of the VPL and  ventral posterior medial (VPM) nuclei as well as in the  zona incerta (ZI). More than 23% re- sponded to esophagus (of 120 neurons examined), 8% to bladder and 6% to colon distension. In contrast to the lateral thalamic neurons, all medial thalamic visceral responsive cells had nociceptive inputs from the skin. In the squirrel monkey, lateral thalamus responses to distending the urinary bladder, distal colon and lower esophagus, as well as to noxiousand innocuous somatic stimuli have been mapped (Brüggemann et al. 1994). Eighty-five percent (of 106 neurons studied) responded to at least one of the viscera. Most visceroceptive cells had somatic low-threshold responses and convergent multivisceral responses. Figure 1 is an example of a neu- ron located in the VPL, it responds to all three viscera by excitationandhasasomatictactilereceptivefieldonfoot digit 5. The visceral responsive cells showed increased or decreased firing for distensions in the noxious range and some also coded distensions in the innocuous and noxious ranges. Figure 2 shows visceral and somatic properties of 20 VPL neurons identified in a single electrode penetration. The extent of unpredictability between adjacent neurons, regarding specific visceral inputs and their excitatory or inhibitory responses is evident. Modulatory effects of visceral stimulation have been examined in squirrel monkey VPL (Brüggemann et al. 1998) and indicate that noxious distensions of urinary bladder, distal colon or lower esophagus de- crease responses to somatic stimuli by about 50%. The high incidence of visceral responsive cells in the VPL implies that this information must be transmitted to the cortex and such visceral responsive neurons have in fact been reported in the monkey primary somatosensory cortex (Brüggemann et al. 1997). Neuronal responses to uterus, cervix, vagina, colon and skin have been examined in the rat thalamus (Berkley et al. 1993; Berkley et al. 1995, Guilbaud et al. 1993). In the lateral thalamus, most neurons responded to mul- tiple viscera and most were located in and around the border of ventrobasal complex (VB). Like results seen inthecatmedialthalamus,mostneuronsinthecaudalin- tralaminar thalamic nuclei (IL) with visceral responses also responded to noxious somatic stimuli, and most had inputs from multiple viscera (Berkley et al. 1995). The lateral portion of ventral medial nucleus (VMl)hasre- Thalamus, Visceral Representation, Figure 1 Visceral responses of a cently been established as a region important in signal- VPL neuron with low-threshold somatic response (touching digit 5, D5 on ing nociceptive information from the brainstem to the the foot contralateral to the recording) in the anesthetized squirrel monkey. cortex (see chapter in this encyclopedia by Villanueva). Intraluminal pressures are shown for each viscus distended. The neuron responds by increased activity to noxious distension of the bladder, colon, Cells in this region respond to noxious mechanical and and esophagus (Bruggemann, Shi and Apkarian 1994). thermal stimuli applied anywhere on the body, yet sur- prisinglytheseneuronsdonotrespondtovisceralstimuli (Monconduit et al. 2003). to any particular viscus (Ganchrow and Erickson 1972; Overall, thalamic nuclei can be differentiated into three Horn et al. 1999). Visceral responsive cells have been kinds: nuclei with visceral specific inputs, nuclei with studied in the medial thalamus of the cat (1995) and visceral convergent inputs and nuclei with no visceral Thalamus, Visceral Representation 2459

inputs. Surprisingly this differentiation does not follow the organization of the thalamus regarding somatic no- ciceptive and non-nociceptive responses, which was a primary hypothesis for most of the studies in the topic. The region of the thalamus presumed to be organized viscerotopically has not been adequately studied, espe- cially physiologically and, although it is commonly re- ferred as the visceral specific part of the thalamus, its de- tailed response properties remain unknown. However, it is possible that the observations in the cat VPL pe- riphery and PO are actually part of the same visceral specificnucleus(VPpc)extendinglaterallyanddorsally. There are important species differences in the visceral organization of the thalamus. In the cat, there is good reproducible evidence that the VPL proper, and most likely also the VPM proper, do not receive visceral in- puts, while the VPL and VPM in rat and monkey do. In fact, in the squirrel monkey there is good evidence that all neurons in the VPL and VPM receive visceral inputs, non-viscerotopically. There is also good agree- ment between studies and across species for medial vis- ceroceptivecellshavingconvergentsomaticnociceptive inputs, while lateral visceroceptive cells have mainly in- nocuous somatic inputs. Given the widely convergent viscero-visceralinputsonsomaticresponsivecellsinthe monkey lateral thalamus, it has been proposed that the visceralinputsthrough dorsalcolumn inputsprovidethe signal for poorly localized visceral perceptions and that the spinothalamic inputs (presumed to be more specific and more dominantly somatic) may then lead to the per- ception of referred pain on the skin; see chapter by Ap- karian in (Gebhart 1995). Undoubtedly, visceral inputs to themedialthalamuswould complementthismodelby providing modulation of affect. The distinct visceral or- ganizational rules of the thalamus, coupled with unique perceptions should provide the opportunity for studying the brain circuitry regarding different types of percep- T tions, yet current research in this field remains limited.

References 1. Bailey P,Bremer F (1938) A sensory cortical representation of the vagus nerve with a note on the effects of the low blood pressure on the cortical electrogram. J Neurophysiol 1:405–412 2. Berkley KJ, Guilbaud G, Benoist JM et al. (1993) Responses of neurons in and near the thalamic ventrobasal complex of the rat to stimulation of uterus, cervix, vagina, colon, and skin. J Neurophysiol 69:557–568 3. Berkley KJ, Benoist JM, Gautron M et al. (1995) Responses of neurons in the caudal intralaminar thalamic complex of the rat to Thalamus, Visceral Representation, Figure 2 Visceral and somatic re- stimulation of the uterus, vagina, cervix, colon and skin. Brain sponses of 20 neurons identified in a single track by an electrode traversing Res 695:92–95 VPL dorso-ventrally. Cell 1 (#) is located most dorsally. Somatic receptive 4. Bester H, Bourgeais L, Villanueva L et al. (1999) Differential fields are either low-threshold tactile (unmarked) or wide-dynamic range projections to the intralaminar and gustatory thalamus from the type marked next to the receptive fields (open circle). Visceral responses parabrachial area: a PHA-L study in the rat. J Comp Neurol are: 0, no response, -, inhibition, +, excitation, ±, mixed; due to distension 405:421–449 of the urinary bladder (B), colon (C), or lower esophagus (E) (missing sym- 5. Brüggemann J, Vahle-Hinz C, Kniffki KD (1993) Representa- bols, not tested; N.A. somatic receptive field not found) (From Bruggemann, tion of the urinary bladder in the lateral thalamus of the cat. J Shi and Apkarian 1994). Neurophysiol 70:482–491 6. Brüggemann J, Shi T, Apkarian AV (1994) Squirrel monkey lat- eral thalamus. II. Viscerosomatic convergent representation of urinary bladder, colon, and esophagus. J Neurosci 14:6796–6814 2460 Thalassotherapy

7. Brüggemann J, Vahle-Hinz C, Kniffki KD (1994) Projections from the pelvic nerve to the periphery of the cat’s thalamic ven- Therapeutic Alliance tral posterolateral nucleus and adjacent regions of the posterior complex. J Neurophysiol 72:2237–2245  8. Brüggemann J, Shi T, Apkarian AV (1997) Viscero-somatic neu- Chronic Pain, Patient-Therapist Interaction rons in the primary somatosensory cortex (SI) of the squirrel monkey. Brain Res 756:297–300 9. Brüggemann J, Shi T, Apkarian AV (1998) Viscerosomatic in- teractions in the thalamic ventral posterolateral nucleus (VPL) Therapeutic Cold of the squirrel monkey. Brain Res 787:269–276 10. Cechetto DF, Saper CB (1987) Evidence for a viscerotopic sen- sory representation in the cortex and thalamus in the rat. J Comp  Therapeutic Heat, Microwaves and Cold Neurol 262:27–45 11. Dell P, Olson R (1951) Projections thalamiques, corticales et cerebelleuses des afferences viscerales vagagles. Soc Biol (Paris) 145:1084–1088 12. Ganchrow D, Erickson RP (1972) Thalamocortical relations in Therapeutic Drug Monitoring gustation. Brain Res 36:298–305 13. Gauriau C, Bernard JF (2004) A comparative reappraisal of pro- jections from the superficial laminae of the dorsal horn in the Definition rat: the forebrain. J Comp Neurol 468:24–56 The use of serum drug concentrations to guide dosing 14. Gebhart GF (1995) Visceral pain. IASP Press, Seattle 15. Guilbaud G, Berkley KJ, Benoist JM et al. (1993) Responses of the drug in order to obtain optimum treatment effect of neurons in thalamic ventrobasal complex of rats to graded and avoid toxicity. distension of uterus and vagina and to uterine suprafusion with  Antidepressants in Neuropathic Pain bradykinin and prostaglandin F2 alpha. Brain Res 614:285–290 16. Horn AC, Vahle-Hinz C, Petersen M et al. (1997) Projections from the renal nerve to the cat’s lateral somatosensory thalamus. Brain Res 763:47–55 17. Horn AC, Vahle-HinzC, Bruggemann J et al. (1999) Responses of Therapeutic Exercise neurons in the lateral thalamus of the cat to stimulation of urinary bladder, colon, esophagus, and skin. Brain Res 851:164–174 Definition 18. Monconduit L, Bourgeais L, Bernard JF et al. (2003) Conver- gence of cutaneous, muscular and visceral noxious inputs onto Exercise as part of a treatment program designed to im- ventromedial thalamic neurons in the rat. Pain 103:83–91 prove an individual’s ability to move, balance and co- ordination, endurance, flexibility, muscle tone, posture, and strength.  Chronic Pain in Children: Physical Medicine and Re- Thalassotherapy habilitation

Definition Therapeutic Gain Bathing in the sea.  Spa Treatment Definition Therapeutic gain is the difference between the therapeu- tic response to the verum and the placebo in a random- Tolosa-Hunt Syndrome (Painful ized controlled trial, in migraine prophylaxis, between the percentage of „responders“, i.e. of patients with a Ophthalmoplegia) 50% reduction of attackfrequency, tothe activedrugand the percentage of responders to placebo.   Headache Due to Dissection Clinical Migraine without Aura

Therapeutic Gene Transfer Therapeutic Acupuncture  Opioids and Gene Therapy Definition Therapeutic Acupuncture refers to the clinical use of acupuncture for the more long-term relief of different Therapeutic Heat symptoms after a course of treatments.  Acupuncture Mechanisms  Therapeutic Heat, Microwaves and Cold Therapeutic Heat, Microwaves and Cold 2461

pads that do not cool spontaneously are convenient but Therapeutic Heat, Microwaves and Cold may increase the risk of burns. JEFFREY R. BASFORD Heat Lamp Department of Physical Medicine and Rehabilitation, Mayo Clinic and Mayo Foundation, Rochester, MN, Heatlampusemaybedecliningbutisstillcommon.Skin USA temperaturesarecontrolledbyadjustingthedistancebe- [email protected] tween the lamp and the patient. The precautions in Table 1 apply to these agents but it should also be noted that Synonyms chronic use of superficial heat can produce a permanent mottling of the skin (erythema ab igne). Physical agent; modality; diathermy; Therapeutic Cold; Therapeutic Heat; Cold Therapy; Microwaves Hydrotherapy Hydrotherapy uses a fluid medium to produce heating, Definition cooling,massageanddebridement.Neitheragitationnor The use of heat and cold to lessen pain, promote healing water is necessary and solutes in the medium (e.g. NaCl or obtain other therapeutic goals. for wound care) may be a significant factor in treatment. Hydrotherapy may also be performed with substances Characteristics such as finely ground solid materials suspended by jets The body is sensitive to its environment. Temperatures of hot air. The benefits of this dry heat ‘fluidotherapy’ above42˚Cor below13˚Cproducediscomfortandthose approach over conventional water-based hydrotherapy only a few degreeshigher or lower may actually injure it. are unestablished. Furthermore,temperaturechangeseasilyobtainedinthe Whirlpool Baths clinic alter enzymatic activity, nerve conduction and tis- sue viscosity (Oosterveld and Rasker 1994). While heat Whirlpoolbathsrangeinsizefromthoseintendedtotreat and cold may be used to alleviate the cause of pain or to asingleextremitytoothersinwhichtheentirebodyisim- produce analgesia, the latter is far more common. mersed. Temperatures of 33–36˚C are usually well tol- Thermal agents achieve their effects as the result of erated, although for a healthy patient, elevations to 43˚C changing the temperature of a tissue. Specifically, most are possible on limited portions of the body. Treatment heat-based treatments attempt to warm tissues to by with stationary mediums may be beneficial. Sitz baths, 3–8˚C and most cold therapies attempt to reduce tis- for example, are beneficial in the treatment of anorectal sue temperatures by a similar amount. As a result, the pain and research demonstrates that bathing at 40–50˚C overlap between their indications and contraindica- is not only comfortable but also lessens anal tone (Pinho tions is surprisingly broad (Tables 1 and 2). It should etal. 1993). Agitation increasestheefficiencyof thermal be remembered that many of the contraindications of transfer and it should be remembered that a temperature heat and cold are relative, i.e. localized heating might that is comfortable with a motionless medium might be- be acceptable in a patient with cardiac disease, while come painfully hot or cold with agitation. systemic heating might place unacceptable demands Contrast Bathing T on his cardiac function (Keast and Adamo 2000). Contrast bathing involves the patient shifting their Mechanism of Action treated extremities alternatively between a warm Tissue can be heated or cooled by conduction, con- (38–40˚C) and a cool (13–16˚C) bath about ten times. vection or the conversion of a different form of energy These baths are frequently used in the treatment of into heat. Hot packs epitomize conductive heating, complex regional pain syndrome with benefits thought hydrotherapy convection and ultrasound conversion, to result from reflex hyperemia and desensitization. due to its reliance on the conversion of sound into heat. ParaffinBaths Superficial Heat Paraffin baths consist of a basin filled with a 1:7 mixture The physiological effects of the superficial heating of mineral oil and paraffin. Temperatures (45–54˚C) are agents differ little and choice depends on the situation higher than those of water-based hydrotherapy and are and patient / therapist preference. tolerated due to the lack of agitation, the insulation pro- vided by wax as it solidifies on the treated area and the Hot Packs low heat capacity of the medium. Treatment is usually Hot packs are typically constructed of porous bags filled performed by dipping the involved extremity in the bath with a hygroscopic material. They are either kept in about ten times, covering it and then allowing it to cool 70–80˚C water baths or warmed in a microwave before slowly in an insulated wrap. An alternative approach in being covered with an absorbent wrap and placed on which the treated extremity is dipped once and then kept the body. Treatments may last for 30 min with the packs in the bath permits more vigorous heating. 30 min treat- slowly cooling. Alternatives such as electrically heated ments may produce increases in the intramuscular tem- 2462 Therapeutic Heat, Microwaves and Cold

Therapeutic Heat, Microwaves and Cold, Table 1 Indications and Precautions for the Use of Therapeutic Heat Indications Precautions and Contraindications

Pain Acceleration of metabolic processes Acute inflammation, trauma or hemorrhage Malignancy Muscle spasm Chronic Hematoma Bleeding dyscrasias Edema Contractures Bursitis / Tenosynovitis Insensitivity Ischemia Fibromyalgia Superficial thrombophlebitis Inability to communicate or respond to pain Atrophic skin / scar tissue Hyperemia Unstable angina or blood pressure Poor thermal regulation (systemic heating situation) Decompensated heart failure / recent myocardial infarction

Therapeutic Heat, Microwaves and Cold, Table 2 Indications and Precautions for the Use of Therapeutic Cold Indications Precautions and Contraindications

Acute musculoskeletal trauma Spasticity Ischemia Severe cold pressor responses Pain Reduction of metabolic activity Cold intolerance / urticaria Inability to communicate or respond to pain Muscle spasm Poor thermal regulation Raynaud’s phenomenon and disease Insensitivity perature of superficial muscles of about 3˚C (Abramson the gravid or mensurating uterus, the heart, brain, cer- et al. 1964). vical ganglia, tumors, laminectomy sites, and acutely inflamed joints. Diathermy  Diathermy can be performed with short waves Short Wave Diathermy (SWD), microwaves (MWD) or ultrasound (USD). Short wave diathermy uses radio waves to heat tis- USD is the most frequently used agent (Lindsay et sue. Use is restricted to a limited range of frequencies al. 1995) but as it is discussed in another chapter will (27.12 MHz, 13.56 MHz and 40.68 MHz in the U.S.). be only summarized here. Discussion here will em- In one approach, the body acts as an antenna and the phasize SWD which is still in relatively widespread SWD machine induces eddy currents that produce heat use and to a lesser extent, MWD whose medical use as they flow through the body. This method delivers is now quite restricted. the most energy to water-rich conductive tissues such as muscles. In the second approach, the body serves Ultrasound as the dielectric of a capacitor that is charged by the Ultrasound has both thermal and  non-thermal effects. SWD machine. In this case, the tissues are in series and The production and effects of heat are well understood. heating may be most marked in water-poor, high re- The benefits of non-thermal processes, which include sistance tissues, such as fat and ligaments. Applicators such phenomena as cavitation (the production and range from inductive pads that are placed on the patient destruction of small bubbles), tissue micro-streaming to the flat plates of a simple capacitor. Although now and mechanical deformation remain to be established. rarely done, specialized heating can be performed by Treatment usually involves stroking an USD applicator wrapping coils around a patient’s limb or with rectal or over the treated tissue for 5–7 min. Intensities range vaginal probes. Continuous waveforms are used when 2 from mWs to 1.5 + W per cm . Continuous waves are the goal is heating while pulsed waves are used when employed when the goal is heating and pulsed treat- non-thermal effects are desired. SWD can increase sub- ments are chosen to emphasize non-thermal effects. cutaneous fat temperatures by 15˚C and 3–5 cm deep Temperature elevations of 5˚C are easily possible and intramuscular temperatures by 4–6˚C (Draper et al. may be particularly large at bone:soft tissue interfaces. 1999). A SWD device is, in effect, a radio transmitter USD phonophoresis is also used to introduce topical that is used to produce heat in two ways. As is true medication (e.g. lidocaine) through the skin. for US, the benefits of SWD non-thermal phenomena USD used as a treatment for conditions ranging from (such as possible frequency dependent effects on cell contractures, sprains, muscle strains, wounds, tendinitis function) remain to be established. and non-healing fractures to carpal tunnel syndrome. Benefits are controversial and in some situations may be Microwaves no more effective than placebos or anti-inflammatories Microwaves(915MHzand2,456MHz)donotpenetrate (Basford 1998). Precautions include those for heat in tissue as deeply as SWD. In fact, their absorption is so general, as well as avoidance of fluid-filled cavities, rapid that fat overlying a site of interest will absorb a sig- Therapeutic Heat, Microwaves and Cold 2463 nificantportionofthebeam.Thus,microwavediathermy efitsintheultimaterecoveryremaindebatabledespiteits (MWD) may increase subcutaneous fat temperatures by ability to lessen metabolic activity and blood flow (Ho 10to12˚C,whiletheunderlyingmuscleswillbewarmed et al. 1995). In practice, ice is typically used in conjunc- only a third as much (Basford 1998). Microwaves have tion with rest, compression and elevation (RICE) in the been replaced in therapy by US and SWD. Today MSD treatment of many musculoskeletal injuries. A common use in medicine appears to be restricted to the produc- regimen, such as for an ankle sprain, consists of using tion of local hyperthermia and the potentiation of cancer ice acutely for about 20 min every 2 h for 6–24 h. Al- chemotherapy and radiation treatment. though icing is almost the automatic response to acute SW and MW diathermy are both subject to the general soft-tissue injury, it may not be a panacea in that studies precautions for heat outlined in Table 1. However, both ofthepostsurgicalknee(Danieletal.1994)andcesarean are electromagnetic in nature and metal implants / de- sections (Amin-Hanjani et al. 1992) may not show ben- vices, pacemakers, stimulators, contact lenses and the efit. menstruating or pregnant uterus should be avoided. After the first day or two, the choice between ice-based Risks are real; diathermy treatment of the jaw resulted therapy and heat appears to depend on personal choice. in severe brain damage in a man with a deep brain Many find heat more comfortable and use it unless stimulator (Nutt et al. 2001). there is a worsening of edema or pain. Others find a combination of icing and active exercising a more ef- Cold Therapy fective way to speed recovery. In any case, long-term Cold decreases metabolic activity, slows nerve conduc- recovery depends on mobilization and exercise. Heat tion, produces analgesia, lessens muscle tone, inhibits and cold are only important as the agents used to assist spasticity and increases gastrointestinal motility (Bas- in gaining it. Patients with long-standing trocanteric ford 1998; Denys 1991). The application of ice to the bursitis and lateral epicondylitis may find ice in combi- body decreases skin temperature by 20˚C in about nation with friction massage extraordinarily effective. 10 min. Subcutaneous temperatures decrease 3–5˚C Ice massage and transcutaneous electrical nerve stim- over the same period. If cooling is continued, forearm ulation (TENS) may be equally beneficial in low back intramuscular temperature may decrease by 6–16˚C pain (Basford 1998). The precautions of Table 2 should and muscle blood flow by as much as 30% (Oosterveld be heeded. Elevation of blood pressure as well as the and Rasker 1994). Although chemical and refriger- effects of cold-induced vasoconstriction in people with ated agents may have temperatures below 0˚C and can ischemiaand Raynaud’sphenomenon maybeimportant produce frostbite, ice treatments of healthy people for considerations. periods of less than 30 min do not seem to cause injury. In summary, there is little evidence that heat and cold alone are of much benefit except for the temporary re- Technique ductionofpain.Asaresult,theyareusuallyprescribedin Ice has a high heat capacity; ice packs, massage, com- conjunction with a program of education, activity mod- pression wraps and slushes all cool tissues rapidly. ification and exercise. Preference plays a role in agent Treatments tend to last 10–20 min and a slightly damp, choicebuttherearesomeguidelinesthatareappropriate. thin towel may be placed between the ice and the skin. Thus, acute musculoskeletal conditions are usually ini- T Iced whirlpools provide particularly rapid cooling. tially treated with ice. In addition, hydrotherapy or SWD However, they are poorly accepted by most people. areusedtotreatlargeareasofthebodywhileUSDisused Insulated foot coverings or fabric socks and gloves may for more focal conditions. Deep heat may appear physi- lessen discomfort and increase acceptance. Ice massage ologically appealing, but at times the comforting effects produces rapid cooling over a limited area. Treatment of superficial heat may prove as beneficial. involves rubbing ice (often pre-frozen in a paper cup) over the painful area. Analgesia can be achieved in 7–10 min. References There are a number of othercooling agents. Vapocoolant 1. Abramson DI, Tuck S, Chu LSW et al. (1964) Effect of paraffin sprays can reduce skin temperature by 20˚C (Oosterveld bath and hot fomentations on local tissue temperatures. Arch Phys Med Rehabil 45:87–94 and Rasker 1994) and are used for local skin analge- 2. Amin-Hanjani S, Corcoran J, Chatwani A (1992) Cold therapy in sia and the “spray and stretch” techniques. Chemical ice the management of postoperative cesarean section pain. J Obstet packscoolviatheproductionofanendothermicreaction Gynecol 167:108–109 and while convenient tend to be expensive. Refrigerated 3. Basford JR (1998) Physical Agents. Rehabilitation Medicine: Principles and Practice, 2nd edn. Lippincott-Raven, Philadelphia, and pressurized water pressure cuffs are also available. pp 483–504 Frozen juice and vegetable packages are convenient for 4. Beenakker EA, Oparina TI, Teelken A et al. (2001) Cooling gar- home use. ment treatment in MS: clinical improvement and decrease in The application of superficial cold appears to lessen hy- leukocyte NO production. Neurology 57:892–894 5. Bert JM, Stark JG, Maschka K et al. (1991) The effect of cold poxic damage, edema and compartmental pressures af- therapy on morbidity subsequent to arthroscopic lateral retinac- ter injury (Bert et al. 1991), but the magnitude of its ben- ular release. Orthop Rev 20:755–758 2464 Therapeutic Relationships

6. Daniel DM, Stone ML, Arendt DL (1994) The effect of cold ther- Hypnotherapy is a term used to describe various forms apy on pain, swelling, and range of motion after anterior cruciate of psychotherapy utilizing hypnosis as the major ingre- ligament reconstructive surgery. Arthroscopy 10:530–533 7. Denys EH (1991) AAEM minimonograph #14: the influence dient. of temperature in clinical neurophysiology. Muscle Nerve Hypnosis has been notoriously difficult to define. The 14:795–811 British Medical Association (1955) introduced the fol- 8. Draper DO, Knight K, Fujiwara T et al. (1999) Temperature lowing operational definition: change in human muscle during and after pulsed short-wave diathermy. J Orthop Sports Phys Ther 29:13–8; discussion 19–22 Hypnosis is a temporary condition of altered perception 9. Ho SSW, Illgen RL, Meyer RW et al. (1995) Comparison of in the subject which may be induced by another per- various icing times in decreasing bone metabolism and blood son and in which a variety of phenomena may appear flow in the knee. Am J Sports Med 23:74–76 spontaneously or in response to verbal or other stimuli. 10. Keast ML, Adamo KB (2000) The Finnish sauna bath and its use in patients with cardiovascular disease. J Cardiopulm Rehabil These phenomena include alterations in consciousness 20:225–230 and memory, increased susceptibility to suggestion, 11. Lindsay DM, Dearness J, McGinley CC (1995) Electrotherapy and the production in the subject of responses and ideas usage trends in private physiotherapy practice in Alberta. Phys- unfamiliar to him in his normal state of mind. Further iother Can 47:30–34 12. Nutt JG, Anderson VC, Peacock JH et al. (2001) DBS and phenomena such as anaesthesia, paralysis and the rigid- diathermy interaction induces severe CNS damage. Neurology ity of muscles, and vasomotor changes can be produced 56:1384–1386 and removed in the hypnotic state. 13. Oosterveld FG, Rasker JJ (1994) Effects of local heat and cold Most investigators emphasise one or more of four char- treatment of surface and articular temperature of arthritic knees. Arthritis Rheum 31:1578–1582 acteristics: expectations and the hypnotist-subject inter- 14. Pinho M, Correa JCO, Furtado A et al. (1993) Do hot baths pro- action; suggestibility;acognitivedimensionrelatedto mote anal sphincter relaxation? Dis Colon Rectum 36:273–274 relaxation and/or  imagery;and dissociation (Evans 2001). Characteristics Therapeutic Relationships Of the wide range of phenomena associated with hyp- nosis, hypnotic analgesia is obviously the most useful  Chronic Gynaecological Pain, Doctor-Patient Inter- in treating pain. Clinicians have typically used one or action more of the following approaches: direct suggestion of pain reduction or insensitivity; suggestions aimed at al- tering the experience of pain; or suggestions directing Therapeutic Ultrasound attention away from pain and its source. Social role theorists have proposed that hypnotic anal-  Modalities gesia is simply a consequence of compliance with the  demand characteristics of the experimental or clin- ical situation. In other words, subjects respond in the way they expect the hypnotist wishes them to respond. Therapy of Pain, Hypnosis However, hypnoticanalgesiashowsamoderately strong ROBERT G. LARGE correlation with measured hypnotic susceptibility (0.5), The Auckland Regional Pain Service, Auckland and there is a marked difference in the subjective expe- Hospital, Auckland, New Zealand rience of subjects simulating hypnosis compared with [email protected] authentic hypnosis (Hilgard and Hilgard 1975). Many studies have shown that pain reduction in response to Synonyms suggestion can occur without any apparent hypnotic in- duction. Nevertheless, accumulating evidence suggests Hypnotism; Mesmerism; Hypnotherapy that a hypnotic induction at least facilitates more pro- found analgesia. Price (1999) proposes that the sense Definition of ease, absorption of attention and lack of monitoring Hypnosis refers to the “state” of consciousness associ- and censoring that are characteristic of hypnosis, lays ated with the phenomenon in question. the foundation for an increased responsiveness to sug- Hypnotism refers to the science and art of inducing and gestion. Modern brain imaging techniques show differ- utilising this phenomenon.This term is now less used in ences in brain activity between normal waking and hyp- current research literature. noticstates.Furthermore,specificanalgesiasuggestions Mesmerism is a term associated with the controversial are accompanied by specific brain changes; e.g. sugges- workofFranzAntonMesmer(1734–1815)andreplaced tions to enhance or reduce pain unpleasantness, with no his concept of “animal magnetism”. Modern accounts change in pain sensation, are accompanied by changes occasionally use the term to describe the non-verbal in the anterior cingulate cortex and not in the primary “mesmeric passes” used in some contexts. sensory cortex. Similarly, suggestions of sensory reduc- Therapy of Pain, Hypnosis 2465 tion produce parallel changes in subjective ratings and pain conditions. It has not been shown to be consistently in activity in the primary somatosensory cortex. There is superior to relaxation or other psychological interven- nowsomeevidencethathypnoticanalgesiaalsoinvolves tions, however. descending brain-to-spinal cord inhibitory mechanisms Hypnosis proved superior to propranalol in children and can inhibit spinal nociceptive reflexes. Our emerg- with migraine, but few other comparisons with drug ing understanding of the nature of hypnotic analgesia is treatments have been made. In studies with adults, that it relates to a wide range of cognitive variables, such hypnosis and  autogenic training appear to be equally as placebo/nocebo, attention, distraction and emotional efficacious for migraine. tone which modulate pain through changes in neural ac- Studies in irritable bowel syndrome have shown not tivity in many brain structures involved in nociception only a reduction in pain and distension, but also changes and pain (Large et al. 2003). in rectal sensitivity assessed by balloon manometry. This finding hints at some basic psychophysiological Treatment for Acute Pain change induced by hypnosis. However, a similar effect Clinicians over many years have reported remarkable on tender points in fibromyalgia was looked for, but not success in using hypnosis to manage acute pain. Mes- found. Work adherence was also improved in a hypnosis mer’s explorations of “animal magnetism” seemed group treated for irritable bowel syndrome, suggesting often to precipitate pain in his patients as an indication an important shift in social and occupational function- of the healing process (Bloch 1980). His followers, such ing. Large and James (1988) found that patients trained as John Elliotson (1791–1868), reported surgical opera- in self-hypnosis changed their  self-constructs as they tions performed under “mesmeric sleep”. James Esdaile gained mastery over their pain. From viewing them- (1808–1859) described 345 operations performed in selves as physically ill people, they moved closer to their India with mesmerism as the sole anaesthetic. Modern construction of their ideal self. This and other studies day accounts of major surgery performed under hyp- suggest that one of the major gains that can be made notic analgesia continue to be collected (Hilgard and through hypnosis is the enhancement of the patient’s Hilgard 1975). Rapid induction techniques have been sense of control and  self-efficacy. Price (1999) points developed for use in managing the acute pain of trauma out that unlike placebo suggestion, which implies an and the imposed pain of procedures (Barber 1982). external authoritative agent, hypnotic suggestion refers Despite its long history and the experience of many clin- to a more innate, internal and self-directed capacity to icians and patients, good outcome research has been alter experience. somewhat sparse. A recent meta-review concluded that Overall, the outcome research on hypnosis is promising, hypnosis had been shown to be effective in controlling but there is a difficulty in relating current clinical ap- the pain of procedures in children with cancer. It is proaches to the results of randomized controlled trials. also effective in reducing the acute pain of burns and Rigorous experimental design favours standardized ap- childbirth (Hawkins 2001). proachestohypnosis,withtheuseofscriptsandprepared tape recordings. In contrast, many clinicians use sophis- Treatment for Chronic Pain ticated and individualized techniques that are difficult to The persistent and relapsing nature of chronic pain replicate across subjects. (Large et al. 2003) For exam- T presents a challenge to the therapist to develop strate- ple, some anecdotal reports have described using hyp- gies that will endure beyond the laboratory or consul- nosis as a means of returning to a presumed crucial trau- tation room. Hypnotic analgesia in the therapy session matic event, so-called  age regression. These reports may offer some respite from pain but not a long-term suggest that resolution of the trauma can lead to a dra- cure. Clinicians have therefore turned to developing matic resolution of a chronic pain problem (e.g. Gainer self-management techniques and the teaching of self- 1992). It is difficult to evaluate the importance of such hypnosis (Eimer 2002). A typical clinical approach is reports in the absence of reports of failures, which are to work with the patient in exploring hypnotic respon- seldom, if ever, published. siveness, emphasizing what is possible rather than what As noted,  hypnotisability is correlated with hypnotic is not possible. Techniques are explored and developed analgesia in laboratory studies. A number of studies in collaboration between therapist and patient. These using hypnosis in chronic pain management have found may range from simple  relaxation,to “special better results in higher hypnotizable subjects. However, place” imagery, to inducing hypnotic analgesia in a it would seem that high hypnotizable subjects are also hand ( glove anaesthesia) and transferring this to the more likely to respond to relaxation techniques in gen- site of pain, to using  post-hypnotic suggestion with eral. This suggests that there are some commonalities or without specific cues. The patient’s own sense of in the various forms of psychological interventions that control is enhanced and encouraged. utilize relaxation. It is possible that highly hypnotisable A review of clinical trials of hypnosis for chronic pain, subjects begin to access the hypnotic state in response to where there has been some attempt at systemisation and relaxation training in general. Hilgard’s research in the control, suggests that hypnosis is effective in a variety of laboratory has suggested that the simple induction of 2466 Thermal Allodynia hypnosis without analgesic suggestions does not induce  Spinal Cord Injury Pain Model, Contusion Injury hypnotic analgesia. Specific analgesic suggestions are Model required. Many relaxation scripts, however, do include suggestions for comfort and pain reduction, so that there is considerable crossover between strategies labelled “hypnosis” and those not labelled “hypnosis”! Thermal Effects of Ultrasound Conclusion Hypnosis has waxed and waned in popularity since the Definition days of Mesmer. Systematic research in cognitive psy- The thermal effects on the target tissue result in an in- chologyandphysiologicalpsychologyhasimprovedour creased local metabolism, circulation, extensibility of understanding of the nature of hypnotic responding and connective tissue, tissue regeneration and bone growth. hypnotic analgesia. The introduction of modern neuro-  UltrasoundTherapyofPainfromtheMusculoskeletal imaging techniques has begun to validate the construct System of hypnosis as a phenomenon that has both subjective and objective reality. Clinical research continues to en- courage the development of effective strategies utilising hypnosis. Hypnosis continues to pose important ques- Thermal Hyperalgesia tions in our understanding of pain, consciousness and cognitive influences on brain processes, as well as chal- lenging us to refine therapeutic strategies utilizing the Definition full potential of hypnotic analgesia. Thermal Hyperalgesia is a condition of altered percep- References tion of temperature. Describes heightened sensitivity to noxious heat. 1. Barber J (1982) Managing Acute Pain. In: Barber J, Adrian C  (eds) Psychological Approaches to the Management of Pain. NeuropathicPain Model, ChronicConstrictionInjury Brunner/Mazel Publishers, New York, pp 168–185  OpioidsintheSpinalCordandModulationofAscend- 2. Bloch G (1980) Mesmerism. A Translation of the Original Scien- ing Pathways (N. gracilis) tific and Medical Writings of F.A. Mesmer. William Kaufmann,  TRPV1, Regulation by Nerve Growth Factor Inc, Los Altos  3. British Medical Association Report (1955) Medical Use of Hyp- TRPV1, Regulation by Protons notism. BMJ 1 Supplement 190 4. Eimer BN (2002) Hypnotize Yourself Out of Pain Now! New Harbinger Publications, Inc, Oakland 5. Evans FJ (2001) Hypnosis in Chronic Pain Management. In: Burrows GD, Stanley RO, Bloom PB (eds) International Hand- Thermal Hyperalgesia Test book of Clinical Hypnosis. John Wiley and Sons, Ltd. Chichester, pp 247–260 6. Gainer MJ (1992) Hypnotherapy for Reflex Sympathetic Dys-  trophy. Am J Clin Hypn 34:227–232 Thermal Nociception Test 7. Hawkins RMF (2001) A Systemic Meta-Review of Hypnosis as an Empirically Supported Treatment for Pain. Pain Rev 8:47–73 8. Hilgard ER, Hilgard JR (1975) Hypnosis in the Relief of Pain. William Kaufmann, Inc, Los Altos 9. Large RG, James FR (1988) Personalised Evaluation of Self- Thermal Neuroablation Hypnosis as a Treatment of Chronic Pain: A Repertory Grid Analysis. Pain 35:155–169 10. Large RG, Price DD, Hawkins R (2003) Hypnotic Analgesia  Radiofrequency Neurotomy, Electrophysiological and its Applications in Pain Management. In: Dostrovsky JO, Principles Carr DB, Koltzenburg M (eds) Proceedings of the 10th World Congress on Pain. Progress in Pain Research and Management, vol 24. IASP Press, Seattle, pp 839–851 11. Price DD (1999) Mechanisms of Hypnotic Analgesia. In: Price DD (ed) Psychological Mechanisms of Pain and Analgesia. Progress in Pain Research and Management vol 15. IASP Press, Thermal Nociception Test Seattle, pp 183–204 1 KENNETH M. HARGREAVES , 2 CHRISTOPHER M. FLORES 1 Thermal Allodynia Department of Endodontics, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA Definition 2Drug Discovery, Johnson and Johnson Pharmaceutical Allodynia evoked by a thermal stimulus. Research and Development, Spring House, PA, USA  Cognitive Behavioral Treatment of Pain [email protected] Thermal Nociception Test 2467

Synonyms testing of selected, individual receptive fields (e.g., Plantar Test; Thermal Hyperalgesia Test; Radiant Heat independent assessment of both hind paws), permitting Test; Hargreaves Test the use of within-subject controls, sophisticated enough to yield a quantifiable, automated end-point, thereby removing most of the potentially confounding observer Definition interaction and sensitive enough to detect relatively The thermal hyperalgesia test permits highly repro- small changes in response to relevant perturbations, ducible evaluation of paw withdrawal thresholds of such as the induction of inflammation and hyperalgesia animals to a beam of radiant heat applied to the plantar and/or the administration of drugs. In 1988, after two surface of the paw. The endpoint is detected automat- years of design, developmentand validation, the plantar ically thereby removing an important potential source test methods paper was published. According to an ISI of observer bias. The test can be used to measure nor- Web of Science™ analysis of papers published through mal nociceptive thresholds and to quantify hyperalgesia May 2005, this paper has been cited in more than 1,000 and allodynia in models of inflammatory or neuropathic publications, making it one of the most heavily cited pain (Hargreaves et al. 1988). articles ever published in the journal Pain (Terajima and Aneman 2003).

Characteristics Procedure Overview The device (for detailed description, see Hargreaves et Our understanding of the chemical and anatomical al. 1988) essentially consists of a raised glass floor be- substrates that underlie hyperalgesia and allodynia neath which is placed a movable case containing a ra- has benefited tremendously from numerous important diant heat source and photoelectric cell that are aimed animal models. Consequently, we have a more pro- through an aperture at the top of the case. The method found appreciation for the processes that contribute involves placing an animal on top of the glass floor and to the development and maintenance of certain be- enclosing it in a small, clear plastic cage. Depending on havioral responses to noxious stimulation and tissue the size of the floor and the enclosuresemployed, several injury. Nonetheless, such models are only as valuable animals may be positioned simultaneously in individual as are the methods employed to detect and quantitate cages. Following an acclimation period, at which point these behavioral responses. Thus, validity, reliability, the animal has come to rest, the aperture is positioned sensitivity, assay reproducibility and flexibility are all directly beneath the plantar surface of the animal’s hind critical determinants of any paradigm by which to assess paw. The trial is commenced by a switch that simultane- nociception and its physiological sequelae. ously activates the heat source and an electronic timer. Attempts to assess pain quantitatively in humans and Uponwithdrawalofthepaw,theresultinginterruptionof animals dates back to the first half of this century, and the reflected light is detected by the photoelectric cell, there are numerous reports of “pain” measurements in thereby signaling the lamp and timer to turn off and a animals responding to thermal, chemical, mechanical or tone to be emitted. The electronic clock circuit is wired electrical stimuli. However, these methods all suffered to a microcomputer and LED readout. The paw with- T from a variety of drawbacks including, but not limited drawal latency (PWL), measured as the time to the near- to, a lack of correlation between human clinical and ex- est 0.1 sec between points at which the switch is turned perimental animal studies, a lack of assay sensitivity to on and the beam of light is interrupted, is taken as a mea- pharmacological manipulation, especially with regard sure of the thermal nociceptive threshold of the animal to  NSAIDs, Survey (NSAIDS), the inability to per- and is displayed on the readout. The test may then be re- form within-subject controls and a virtually uniform re- peatedonthesameortheotherpaw.Owingtothefactthat liance on non-complex, reflex behaviors (often involv- the procedure is carried out on unrestrained, freely mov- ing the uniquely scaly, non-glabrous skin of the rat tail) ing animals, this method also allows for the concurrent that are difficult if not impossible to equate with the hu- measurement of complex, organized behaviors in addi- mansensationofpain. tion to the PWL, including the duration and rapidity of The plantar test avoids many of these limitations since withdrawal as well as various locomotor activities such it measures complex, nociceptive behaviors follow- as licking, each a separate measure of hyperalgesia (de- ing thermal stimulation of cutaneous tissues, using fined as an exaggerated response to a noxious stimulus). a method allowing for not only the determination of To measure duration of paw withdrawal, a stopwatch is thermal nociceptive thresholds but also the quantitation started when the device emits the tone and is stopped of  primary hyperalgesia,  secondary hyperalgesia when the paw is returned to the glass floor. Similarly, and  allodynia. The test is performed in awake, freely the duration of licking or other complex behavior can moving and unrestrained animals, thereby avoiding the be measured. Changes in latency correspond to thermal potential generation of stress responses. In addition, allodynia, since latency is directly correlated with cuta- the device is flexible enough to permit the independent neous temperature (Fig. 1). In contrast, changes in du- 2468 Thermal Nociception Test

Thermal Nociception Test, Figure 1 Effects of radiant heat on the cu- taneous temperature of rat hind paws. Reproduced with permission from: Hargreaves, et al. Pain 32:77-88, 1988, Elsevierl’. ration of hind paw elevation following the stimulus may reflect aspects of hyperalgesia (Fig. 2).

Advantages and Disadvantages Many of the advantages and limitations of this radiant heatmethodcomparedwithpreviouslyexistingmethods have been summarized (Table1).Perhapsof greatestim- portanceisthatthisparadigm conformstotheguidelines for the ethical and responsible use of animals as exper- imental subjects established by the International Asso- ciation for the Study of Pain and the Society for Neu- roscience. In this regard, it is of profound importance that the noxious stimulus applied during testing of the animals is readily escapable. Thus, the animal itself ter- minates the experimental session after a brief stimulus and before any thermal injury can occur, even after re- Thermal Nociception Test, Figure 2 (a) Effects of carrageenan on the peated application of the test. In addition, the capacity to latency for hind paw withdrawal following injection of carrageenan into perform the test on an awake, freely moving animal that one hind paw with measurement of both the ipsilateral injected hind paw appears ostensibly calm and comfortable during the ac- and the contralateral control hind paw. (b) Effects of carrageenan on the climation and testing period markedly reduces the con- post-stimulus duration of hind paw elevation above the glass floor in the same animals as (a). Reproduced with permission from: Hargreaves et al. cern that any stress-related neuroendocrine circuits will Pain 32:77-88, 1988, Elsevierl’. be engaged. Another advantage to the freedom of move- ment afforded by this method is that a number of more complex behaviors related to an induced hyperalgesic state and occurring secondary to or as a result of the test- responsiveness to noxious stimulation. It is also theo- ing can be measured. The ability to quantitate such an retically possible to alter the device to deliver a sub- array of nociceptive behaviors gives rise to a “hyperal- threshold stimulus as a means of measuring allodynia. gesiaprofile”foragivenanimalthatmaybecomparedto In the context of this discussion then, it may be ap- other individuals under a variety of experimental condi- preciated that this method is amenable to measuring tions. Thisset-up also readily permitsthe administration hyperalgesia that develops due to inflammation or nerve of test articles or other perturbations, on a repeated basis injury induced by a variety of perturbations. Thus, the if necessary, in between PWL measurements. method has been applied to several models, including As already alluded to, this method, in addition to the intraplantar injection of carrageenan (Hargreaves et measuring thermal nociceptive thresholds in normal al. 1988), complete Freund’s adjuvant (Iadarola et al. animals/hind paws, may also be used to quantitate 1988), yeast (Iadarola et al. 1988), nerve growth factor hyperalgesia, operationally defined as an increased (Andreev et al. 1995) or the induction of a peripheral Thermal Nociception Test 2469

Thermal Nociception Test, Table 1 Methodological Papers Evaluating the Radiant Heat Divice Modification of Parameter Evaluated Authors

Methods paper: thermal hyperalgesia in a model of inflammation Hargreaves et al. 1988

Thermal hyperalgesia in a model of peripheral neuropathy Bennett and Xie 1988

Glass surface acts as a heat sink Hirata et al. 1990

To avoid heat sink effect, only test a paw when it is in contact with the glass surface Bennett and Hargreaves 1990

A nylon mesh over the glass surface reduces the heat sink effect Murphy et al. 1991

Animals restrained during thermal testing Kerns et a1. 1991

Testing thermal thresholds in normal animals Yamamoto and Yaksh 1991

Heated glass surface using feedback control to avoid a heat sink effect Yamamoto and Yaksh 1991

Correlation of paw temperature and escape latencies are consistent with measuring nociception Yeomans et al. 1992

Thermal hyperalgesia in a model of peripheral neuropathy Kim and Chung 1992

Thermal hyperalgesia following i.t. NMDA Malmberg and Yaksh 1993

Heated glass floor, joystick control of radiant heat source, illustration of a circuit diagram Galbraith et al. 1993

Radiant heat device more sensitive than tail flick for detecting thermal hyperalgesia during tolerance Mao et al. 1994

Frogs as test subject Willenbring and Stevens 1995

Radiant heat applied to the dorsum of the hindpaw Tracey et al. 1995

Gerbils as test subject Rupniak et aI. 1995

Evaluated two intensities of radiant heat in the same subjects Abram and O’Connor 1995 neuropathy by nerve constriction (Bennett and Xie ability to correlate somatotopically localized biochem- 1988; Kim and Chung 1992; Bennett 1999). ical, cellular and molecular alterations with behavior One of the most important advantages of this method in the affected limb. Thus, several interesting studies compared with previous methods is the ability to have were performed in which carrageenan- or CFA-induced within-subject controls. This may be represented sta- hyperalgesia was correlated with somatotopically ap- tistically as left vs right or baseline vs post-perturbation propriate increases in opioid peptide gene expression hind paw difference scores. The utility of this transfor- in the dorsal spinal cord on the side ipsilateral to the mation of the data is highlighted by the demonstration inflammation (Iadarola et al. 1988). In addition, in vivo T of Bennett and Xie that 140 normal rats exhibited differ- microdialysis has been used to measure and correlate ence scores that fit a Gaussian distribution with a mean the time course of the local production and/or release and standard deviation of 0.04 ± 0.66 sec (i.e. a right- of inflammatory mediators with nociceptive behavior left difference score of approximately zero) (Bennett in parallel groups of animals (Hargreaves and Costello and Xie 1988). This feature of the paradigm has been 1990). exploited in myriad, within-animal studies evaluating Ultimately, the true measure of any method rests on its the mechanisms of hyperalgesia and inflammation and sensitivity, in other words, the ability to detect changes the effects of drugs or other therapeutic interventions in the dependent measurement when in fact they occur. used to counteract these processes. Thus, one could de- In this respect, it is significant that in the periphery, the sign a study to determine whether a given inflammatory sensitivity to detect hyperalgesia is greater for thermal agent results in a localized vs systemic hyperalgesia. In vs mechanical stimuli in several tests (Handwerker et addition, one could distinguish between peripheral vs al. 1987). Consistent with this concept, the radiant heat central mechanisms of action of antinociceptive agents device was shown to be more sensitive than the Ran- (Jackson et al. 1995), in that PWL measurements can be dallandSelittomechanicaltestindetectinghyperalgesia made in a given paw following injection of a potentially in response to a subcutaneous injection of carrageenan, antinociceptive test substance directly into that paw or which was manifested as an increase in signal-to-noise alternatively into the contralateral paw or some other ratios, asindicated by improved ANOVAF ratiosand in- remote location, usually at a dose that is not sufficient creased carrageenan dose-response curve slopes (Harg- to reach pharmacologically relevant systemic con- reaves et al. 1988). Moreover, the radiantheatdevice has centrations. Another application of this method is the been used to evaluate several hundred compounds, rep- 2470 Thermal Receptors resenting at least 20 distinct classes for their ability to al- rophysiolgical underpinnings of pain in humans and ter nociception and nociceptive behaviors, highlighting ultimately better treatment options. its utility as a tool not only for investigating the neuro- chemistry of pain but also for the development of novel References analgesic therapeutics. 1. Andreev NY, Dimitrieva N, Koltzenburg M et al. (1995) Periph- The most obvious limitation of the current method is eral administration of nerve growth-factor in the adult-rat pro- that it does not measure mechanical nociceptive thresh- duces a thermal hyperalgesia that requires the presence of sym- olds, allodynia or hyperalgesia. Moreover, the extent pathetic postganglionic neurons. Pain 63:109–115 to which thermal hypersensitivity, as measured by this 2. Bennett GJ (1999) Does a neuroimmune interaction contribute to the genesis of painful peripheral neuropathies? Proc Natl Acad method, accurately predicts the efficacy of clinically Sci USA 96:7737–7738 useful drugs (based on type 1 and type 2 errors) or 3. Bennett GJ, Hargreaves KM (1990) A model of peripheral reliably mimics one or more than one clinically rele- mononeuropathy in the rat – reply. Pain 42:255–255 4. Bennett GJ, Xie Y-K (1988) A peripheral mononeuropathy in vant pain condition/symptom remains to be determined rat that produces disorders of pain sensation like those seen in (although the test reliably demonstrates the efficacy of a man. Pain 33:87–107 variety of currently marketed NSAID and opioid anal- 5. Galbraith JA, Mrosko BJ, Myers RR (1993) A system to measure gesics with reasonably appropriaterank order potency). thermal nociception. J Neurosci Methods 49:63–68 6. Handwerker HO, Anton F, Kocher L et al. (1987) Nociceptor Notwithstanding these caveats, the combination of the functions in intact skin and in neurogenic or non-neurogenic in- thermal method with mechanical tests, such as the use flammation. Acta Physiol Hung 69:333–342 of von Frey filaments, offers a powerful approach to 7. Hargreaves KM, Costello A (1990) Glucocorticoids suppress lev- the study of a variety of nociception-modifying pertur- els of immunoreactive bradykinin in inflamed tissue as evaluated by microdialysis probes. Clin Pharmacol Ther 48:168–178 bations as well as a means for discriminating potential 8. Hargreaves KM, Dubner R, Brown F et al. (1988) A new and sensory modality differences between them. The other sensitive method for measuring thermal nociception in cutaneous major disadvantage of the radiant heat method is that the hyperalgesia. Pain 32:77–88 glass surface may act as a heat sink, leading to artifac- 9. Hirata H, Pataky A, Kajander K et al. (1990) A model of pe- ripheral mononeuropathy in the rat. Pain 42:253–254 tually short paw withdrawal latencies and a subsequent 10. Iadarola MJ, Brady LS, Draisci G et al. (1988) Enhancement of increase in assay variability (Bennett and Hargreaves dynorphin gene-expression in spinal-cord following experimen- 1990; Hirata et al. 1990). This factor will vary with the tal inflammation – stimulus specificity, behavioral parameters specific conductive properties of the floor, the ambient and opioid receptor-binding. Pain 35:313–326 11. Jackson DL, Graff CB, Richardson JD et al. (1995) Glutamate temperature in the experimental procedure room and participates in the peripheral modulation of thermal hyperalgesia the pressure exerted by the rat on the paw being tested, in rats. Eur J Pharmacol 284:321–325 which last will be affected under conditions of induced 12. Kim SH, Chung JM (1992) An experimental-model for peripheral neuropathy produced by segmental spinal nerve ligation in the inflammation or neuropathy (Bennett and Hargreaves rat. Pain 50:355–363 1990; Murphy et al. 1991). However, several sugges- 13. Murphy LG, Alexander GM, Schwartzman RJ (1991) Improve- tions have been made to counteract this effect, the most ment to the Hargreaves paw flick method. Pain 46:347–347 important of these being that the skin being irradiated 14. Terajima K, Aneman A (2003) Citation classics in anaesthesia and pain journals: a literature review in the era of the internet. should be in contact with the glass floor (Table 1). Mod- Acta Anaesth Scand 47:655–663 ifications to the device itself include placing a nylon mesh screen between the rat and the glass (Murphy et al. 1991) or heating the floor to maintain it at a constant temperature, either by implanting a heating element within the glass or applying warm air to its underside Thermal Receptors (Galbraith et al. 1993). The minor inconveniences cre- ated by the rats urinating or defecating on the glass floor are easily remedied with a spray bottle of cleanser and Definition a roll of paper towels. Sensory receptors sensitive to thermal stimuli. In conclusion, the radiant heat test described here  Hyperaesthesia, Assessment offers a simple, highly reproducible and useful ap-  Hypoesthesia, Assessment proach to the study of thermal nociception in naïve and injured/inflamed rodents. Accordingly, it may be considered one of several powerful behavioral tools available to pain scientists in the investigation of noci- ceptive mechanismsand inthesearchforbetterandsafer Thermal Sensory Testing analgesic drugs. It is hoped that further improvements in this method, including those mentioned herein, and its use in combination with complementary behavioral  Quantitative Thermal Sensory Testing of Inflamed assays will lead to a better understanding of the neu- Skin Theta Rhythm 2471

The surface temperature is measured with a thermocou- Thermal Stimulation (Skin, Muscle, ple or thermister, which is used in a feedback manner to Viscera) regulate the thermode’s surface temperature.  Threshold Determination Protocols  Pain in Humans, Thermal Stimulation (Skin, Muscle, Viscera), Laser, Peltier, Cold (Cold Pressure), Radi- ant, Contact Thermography

Definition Thermal Stimulation (Stimuli) Detects and delineates areas of cutaneous thermal change. Definition  Postoperative Pain, Acute Presentation of Complex Thermal stimulation (warm and cold stimuli) consists Regional Pain Syndrome of transferring (adding or subtracting) calorific energy between the skin (or mucosa, muscle, viscera) and its surroundings. Thermoreception  Causalgia, Assessment  Dysesthesia, Assessment   Pain in Humans, Thermal Stimulation (Skin, Muscle, Lateral Thalamic Pain-Related Cells in Humans Viscera), Laser, Peltier, Cold (Cold Pressure), Radi- ant, Contact Thermoreceptor

Thermal Therapy Definition Cutaneous, oral and visceral receptors responding only  Spa Treatment or preferentially to temperature within the innocuous or nonpainful range. Thermoreceptors show static and dy- namic sensitivity to temperature.  Thermal Transduction Nociceptors, Cold Thermotransduction

 Polymodal Nociceptors, Heat Transduction Thermoregulation

Definition T Thermocoagulation Rodentsregulatebodytemperaturemainlybyregulating blood flow in the tail by an on-off mechanism, suddenly Definition changing the tail skin temperature by up to 8–10˚C. Destroying tissue (e.g. nerves) by heating.  Tail-Flick Test  Cancer Pain Management, Anesthesiologic Interven- tions, Neural Blockade  Radiofrequency Neurotomy, Electrophysiological Theta Rhythm Principles Definition Thermode Frequency domain of oscillatory hemispheric activity between 4 and 8 Hz. It has been associated with different functional brain states, e.g. somnolence, cognitive acti- Definition vations, altered states of consciousness like meditation, A thermode is a device used to apply controlled temper- and, relevant here, dysfunctional brain states like neuro- ature to the skin of subjects or animals. One surface of genic pain and tinnitus, abnormal movements, epilepsy the thermode is placed in contact with the skin. The tem- and neuropsychiatric disorders (see thalamocortical perature at that surface is controlled with the use of heat- dysrhythmia). ing elements, Peltier elements, and/or circulating water.  Thalamotomy for Human Pain Relief 2472 Thoracic Epidural Analgesia

only means of determining if they are a source of pain Thoracic Epidural Analgesia is to anaesthetise putatively symptomatic joints. The thoracic zygapophysial joints can be anaesthetised Definition either by injecting local anaesthetic into the joint cav- ity, or by anaesthetising the medial branches of the dor- Pain relief obtained by drugs acting directly on the sal rami that innervate them. Respectively, these proce- spinal cord, e.g. morphine, local anesthetics, adrenaline dures are called thoracic intra-articular zygapophysial (epinephrine), clonidine, and neostigmine. joint blocks and thoracic medial branch blocks.  Postoperative Pain, Acute Pain Management, Princi- ples Intra-Articular Block  Postoperative Pain, Acute Pain Team The thoracic zygapophysial joints are not directly evi- dent on anteroposterior views of the thoracic spine, be- causetheirjointcavitiesareorientatedinacoronalplane. Nevertheless, the location of each joint can be inferred. Thoracic Epidural Anesthesia The joint lies opposite the inter-vertebral disc of the seg- ment, between the pediclesofthe twovertebraethatcon- tribute to the joint. Definition Oncethetargetjointhasbeenidentified,apuncturepoint For thoracic epidural anesthesia the catheters are in- on the skin is selected, about three-quarters of a seg- serted dependent on the surgical procedure, between ment caudal to the joint, on a caudal extension of the level T4–T12 by a median or paramedian approach and sagittal bisector of the pedicle below the target joint. A usually with the loss of resistance technique. Postop- spinal needle is introduced at around 60 degrees caudal eratively, the patient has perfect analgesia and can be to the perpendicular, and is advanced towards the lower mobilized. quarter of the silhouette of the pedicle below the joint  Postoperative Pain, Thoracic and Cardiac Surgery (Dreyfuss et al. 1994; International Spinal Intervention Society 2004a). A contra-lateral oblique view can then be used to carefully advance the needle into the inferior margin of the joint (Fig. 2a). Once the needle has en- Thoracic Medial Branch Blocks and tered the joint, an anteroposterior view is used in order to check that the needle has not strayed medially or lat- Intra-Articular Blocks erally (Fig. 2b). PAUL VERRILLS Intra-articular placement is verified by injecting 0.1 ml Metropolitan Spinal Clinic, Prahran, VIC, Australia of contrast medium, in order to obtain an arthrogram [email protected] (Dreyfuss et al. 1994; International Spinal Intervention Society 2004a) (Fig. 3). Subsequently,the joint is anaes- thetised by injecting 0.75 ml of local anaesthetic. Synonyms Intra-Articular Blocks and Thoracic Medial Branch Medial Branch Block Blocks The thoracic medial branches cross the thoracic trans- verse processes obliquely, passing from theregion of the Definition superior lateral corner of the process to its infero-medial corner. At segmental levels T1–4 and T9 and T10, the Thoracicmedialbranchblocksandintra-articularblocks nerves lie on the posterior surface of the transverse pro- are both diagnostic procedures designed to test if the pa- cess,slightlybelowandjustmedialtothesuperiorlateral tient’s pain arises from a thoracic zygapophysial joint. corner of the transverse process. This point constitutes They involve anaesthetising the joint or its nerve supply the target point for medial branch blocks at these levels with injections of small volumes of local anaesthetic. (Chua and Bogduk 1995; International Spinal Interven- tion Society 2004b). Characteristics Under postero-anterior fluoroscopic screening, a spinal Thethoraciczygapophysialjointsmaybeacauseofpos- needle is inserted through the skin of the posterior tho- terior thoracic spinal pain. Studies in normal volunteers rax, and passed towards the target point of the nerve (Dreyfussetal. 1994), andinpatients(Fukuietal.1997), to be blocked (Fig. 4). Once the needle has reached have shown that noxious stimulation of these joints pro- bone, a test-dose of contrast medium is injected un- duces local and  somatic referred pain in a segmental der continuous fluoroscopic screening to ensure that pattern along the posterior chest wall (Fig. 1). there is no vascular uptake, and to determine that the There are no means clinically, or by medical imaging, injectate spreads appropriately (International Spinal by which pain from these joints can be diagnosed. The Intervention Society 2004b). To block the nerve, 0.3 ml Thoracic Medial Branch Blocks and Intra-Articular Blocks 2473

Thoracic Medial Branch Blocks and Intra-Articular Blocks, Figure 1 The distribution of referred pain from the thoracic zygapohysial joints. Based on Dreyfuss et al. 1994 and Fukui et al. 1997. T of local anaesthetic is injected. To anaesthetise a given Evaluation zygapophysial joint, both the nerves that innervate it are blocked. The optimal means of reducing error and securing reli- AttheT4toT8levels,themedialbranchesdonotrunon able diagnostic information is real time assessment. The bone.Fromtheintertransversespace,theyaresuspended response to the diagnostic block is evaluated immedi- dorsal to the depth of the transverse process (Chua and ately after the block, and for some time afterwards, at Bogduk 1995). In order to block the nerve, a needle is the clinic at which the block was performed, and by an delivered into the intertransverse space, slightly cranial independent observer using validated and objective in- to the tip of the transverse process (International Spinal struments or tools (Dreyfuss et al. 1994; International InterventionSociety2004b).Inthislocation,asmallvol- Spinal Intervention Society 2004b). ume of contrast medium is injected, in order to confirm Visual analogue scores are recorded before the block, appropriate spread of injectate. Thereupon, local anaes- immediately afterwards, at 30 minutes and then hourly. thetic can be injected to anaesthetise the nerve. The patient is instructed to monitor the extent and du- The T11 and T12 medial branches assume a course sim- ration of any relief that ensues. Further, if relief occurs, ilar to that of the lumbar medial branches. The target the patient should carefully attempt movements and ac- points and technique for these nerves are like those for tivities that are usually restricted by pain to assess their  lumbar medial branch blocks. response during the anaesthetic phase. 2474 Thoracic Medial Branch Blocks and Intra-Articular Blocks

Thoracic Medial Branch Blocks and Intra-Articular Blocks, Figure 2 Radiographs of a needle in position for an intra-articular injection of a thoracic zygapophysial joint. (a) Lateral view. (b) AP view. Reproduced courtesy of the International Spinal Intervention Society (2004a).

If the response to the block is negative, then zy- Nerve Blocks). Complete relief of pain on each of the gapophysial joint pain can effectively be ruled out two occasions, regardless of duration of relief, increases at the level tested. Adjacent levels may then be blocked the positive yield of blocks, but increases the risk of based on clinical indication. false-positive responses. If the response to the block is positive, then a control Similar controls have not been evaluated for intra- block is undertaken. If the patient has a concordant re- articular blocks. Their validity has not been established. sponse to controlled blocks, then the putative diagnosis of zygapophysial joint pain is confirmed. Application Only one study has described the application of thoracic Validity medial branch blocks in clinical practice (Manchikanti Single diagnostic blocks of thoracic medial branches et al. 2002). It reported that 48% of patients had their carry a false-positive rate of 58% (Manchikanti et pain relieved with the medial branch blocks. The study al. 2002). Control blocks are, therefore, mandatory thereby established that thoracic zygapophysial joint (International Spinal Intervention Society 2004b; blocks have a considerable diagnostic utility in clinical Manchikanti et al. 2002). practice. However, it did not indicate which segmental Although placebo controlled blocks could be used, levels were most commonly the source of pain. they require three injections, and are not readily imple- By analogy, with lumbar and cervical spine, one would mented in clinical practice. Comparative local anaes- expect the therapeutic utility of thoracic medial branch thetic blocks, using lignocaine 2%, as a short-acting blocks would be to select patients for medial branch agent, and bupivacaine 0.5% as a long-acting agent, are  radiofrequency neurotomy.However,thereareno a valid alternative (International Spinal Intervention publications to describe a valid technique, or to es- Society 2004b; Manchikanti et al. 2002; Barnsley et tablish the efficacy of such treatment in the thoracic al. 1993;Lord etal.1995).Aconcordantresponse would spine. Therefore, the therapeutic utility of thoracic be complete relief of pain for a shorter duration fol- zygapophysial joint blocks is only potential. lowing the short-acting agent, and a longer duration of Although intra-articular blocks constitute an alternative relief following the long-acting agent (see  Peripheral means of diagnosing thoracic zygapophysial joint pain, Thoracic Medial Branch Blocks and Intra-Articular Blocks 2475

no studies have described any results from their use. Some operators administer intra-articular injections of corticosteroidsasatreatmentforthoraciczygapophysial joint pain, but no studies have reported the efficacy of this treatment.

Patient Selection Thoracic zygapophysial joint blocks are not indicated in acute pain. They are relevant only for patients with persistent thoracic spinal pain, in whom a diagnosis is required. A prerequisite is that serious possible causes of pain such as infection, tumours, vascular disease and metabolic disease have been excluded by careful and thorough history and examination, laboratory tests, and medical imaging if necessary. The working diagnosis should be that of thoracic spinal pain of unknown origin. The minimum criterion should be that the patient has pain in a distribution that resembles that shown to em- anate from thoracic zygapophysial joint in normal vol- unteers (Dreyfuss et al. 1994; Fukui et al. 1997).

Contraindications Absolute contra-indications include bacterial infection, Thoracic Medial Branch Blocks and Intra-Articular Blocks, Figure 3 either systemic or localised in the region that blocks are A lateral radiograph of an arthrogram of a thoracic zygapophysial joint. The to be performed, bleeding diatheses or possible preg- arrows point to contrast medium inside the joint. Reproduced courtesy of nancy. Relativecontraindicationsincludeallergy tocon- the International Spinal Intervention Society (2004a). trast media or local anaesthetics.

References 1. Barnsley L, Lord S, Bogduk N (1993) Comparative Local Anaes- thetic Blocks in the Diagnosis of Cervical Zygapophysial Joint Pain. Pain 55:99–106 2. Chua WH, Bogduk N (1995) The Surgical Anatomy of Thoracic Facet Denervation. Acta Neurochir 136:140–144 3. Dreyfuss P, Tibiletti C, Dreyer SJ (1994) Thoracic Zygapophy- T seal Joint Pain Patterns. A Study in Normal Volunteers. Spine 19:807–811 4. Dreyfuss P, Tibiletti, C, Dreyer S, Sobel J (1994) Thoracic Zygapophysial Joint Pain: A Review and Description of an Intra–Articular Block Technique. Pain Digest 4:46–64 5. Fukui S, Ohseto K, Shiotani M (1997) Patterns of Pain Induced by Distending the Thoracic Zygapophyseal Joints. Regional Anes- thesia 22:332–336 6. International Spinal Intervention Society (2004a). Thoracic In- tra–Articular Zygapophysial Joint Blocks. In: Bogduk N (ed). Practice Guidelines for Spinal Diagnostic and Treatment Proce- dures. International Spinal Intervention Society, San Francisco (in press) 7. International Spinal Intervention Society (2004b). Thoracic Medial Branch Blocks. In: Bogduk N (ed) Practice Guidelines for Spinal Diagnostic and Treatment Procedures. International Spinal Intervention Society, San Francisco (in press) 8. Lord SM, Barnsley L, Bogduk N (1995) The Utility of Compara- Thoracic Medial Branch Blocks and Intra-Articular Blocks, Figure 4 tive Local Anaesthetic Blocks versus Placebo–Controlled Blocks An AP radiograph showing a needle in place for a thoracic medial branch for the Diagnosis of Cervical Zygapophysial Joint Pain. Clin J block, and an injection of contrast medium to show spread of injectate Pain 11:208–213 over the superior lateral corner of the transverse process. The inferior 9. Manchikanti L, Singh V, Pampati V, Beyer CD, Damron KS border of the transverse process (TP) is labelled. Reproduced courtesy of (2002) Evaluation of the Prevalence of Facet Joint Pain in Chronic the International Spinal Intervention Society 2004a. Thoracic Pain. Pain Physician 5:354–359 2476 Thoracic Outlet Syndrome

Thoracic Outlet Syndrome 1, 2 A. LEE DELLON 1Plastic Surgery and Neurosurgery, Johns Hopkins University, Baltimore, MD, USA 2Plastic Surgery, University of Arizona, Tucson, AZ, USA [email protected]

Synonyms Brachial Plexus Compression; Scalenus Anticus Syn- drome; Costoclavicular Syndrome Definition Thoracic Outlet Syndrome is a misnomer for the symp- toms caused by compression of the brachial plexus in the thoracic inlet. The symptoms have a wide range that can encompass any manifestation related to the motor or sensory functions of the cervical nerve roots C5, C6, C7, C8, and T1. There can be secondary symptoms re- lated to the cervical plexus and shoulder dysfunction. The most common symptoms are aching in the shoul- der, numbness in the fingers, with the symptoms being aggravated or initiated by elevating the arm above the shoulder level. The syndrome most commonly occurs in the setting of neck or shoulder trauma, and is often related to the presence of anatomical congenital anoma- lies. Due to the inability of traditional electrodiagnostic testing to identify this syndrome, except for the isolated Thoracic Outlet Syndrome, Figure 1 Brachial Plexus Neurolysis. problem with the lower trunk of the brachial plexus, di- agnosis and treatment for brachial plexus compression in the thoracic inlet remains a controversial source of but can be associated with compression of the brachial neck, shoulder and upper extremity pain. plexus in this same region (Mackinnon and Dellon 1988; Leffert 1992). The classic physical examination Characteristics maneuvers related to the disappearance of the radial The subclavian artery and subclavian vein exit the tho- pulse when the hand is elevated or the head is turned, rax and enter the upper extremity by a path that takes are best related to the arterial form of compression in them into the supraclavicular region, and then between this region, but can be present in 33% of the normal the clavicle and the first rib and into the axilla. The an- population. terior scalene muscle is usually located between these When the lower trunk of the brachial plexus, formed two large blood vessels as it inserts into the first rib. from the C8 nerve root and T1 nerve root, are com- Post-traumatic tightness or anatomic anomalies in this pressed against the posterior border of the first rib by region can cause vascular symptoms such as purplish a tumor (Pancoast Syndrome, upper pulmonary lobe color and swelling due to venous obstruction, or cold- bronchogenic carcinoma, or benign neural tumor like ness and digital necrosis due to arterial obstruction and Schwannoma or neurofibroma), trauma, or congenital emboli. These vascular forms of the “thoracic outlet anomaly, the patient experiences symptoms of coldness syndrome” are responsible for about 5% of the patients in the arm, apart from subclavian artery compression with symptoms in this region, and the diagnosis is made (because the sympathetic input from the stellate gan- by radiologic imaging of these vessels with the arm at glion enters the lower trunk). They also experience rest and the arm elevated. These vessels actually leave numbness of the little and ring finger, as well as the the thorax, and pass across the thoracic inlet to reach the upper inner arm, and intrinsic muscle weakness, be- axilla (Fig. 1). Relief of obstruction is surgical, requir- cause these are the skin territories innervated by these ing resection of the anterior scalene muscle or excision nerve roots, and all the intrinsic muscles of the hand of the first rib. Different anatomic approaches, supra- are innervated by these nerve roots. Note that the com- clavicular or transaxillary, are currently in use. These pression site is at the thoracic inlet (the thoracic outlet vascular syndromes do not have neurologic symptoms, is the diaphragm). Therefore, this is the one form of Thoracic Outlet Syndrome 2477 thoracic outlet syndrome that can be identified by elec- Diagnosisofbrachialplexuscompressioninthethoracic trodiagnostic testing (EDT) (Gilliatt et al. 1970). The inlet has been a challenge. Traditional EDT cannot iden- EDT will demonstrate abnormal electromyography tify this compression because the site is too close to the of both median and ulnar nerve innervated intrinsic spinal nerve roots, because the variation in thickness of muscles (typically the abductor digiti minimi, the first the chest wall invalidates amplitude measurements, and dorsal interosseous, and the opponens pollicis and the because the inability to measure distance variable inval- abductor pollicis brevis), with a decreased sensory idates nerve conduction measurements. The H-wave is amplitude for the little finger while the sensory am- notreliablebecauseastheimpulsetravelsfromthefinger plitude remains normal for the index finger. This “true to the spinal cord and back to the hand, multiple poten- neurogenic” thoracic outlet syndrome is rare, account- tialsitesofentrapmentareencounteredatthewrist,fore- ing for less than 1% of patients with thoracic outlet arm and elbow. (Wilbourn and Urschel 1984) Since the syndrome. symptoms are produced or aggravated when the hands Thevastmajority of patients(94%) havecomplaintsthat are elevated above the head, provocation of the plexus in are often global in nature, which has led some to doubt suchamannerhasbeenusedtoidentifypatientswiththo- theexistenceofthissyndrome(CheringtonandChering- racicoutletsyndrome, apositiveRoossign (Roos1966). ton 1992; Roos and Wilbourn 1990). Headaches, shoul- Palpation over the brachial plexus in the thoracic inlet der pain, diffuse weaknessin theupperextremity,numb- will produce a distally radiating sign when the plexus is ness in the little and ring finger, but also in all fingers, compressedbeneathanatomicstructuresinthislocation, and these symptoms being made worse by any activity positive Tinelsign or pressureprovocativetest(Novaket that requires elevation of the shoulder. In some women al. 1995). Based upon the assumption that measurement there is breast pain. In some patients there is upper back ofthecutaneouspressurethresholdwouldchangeforthe orscapularpain.Insomepatientsthereispaininthetem- index finger (representing the upper trunk) and the little poromandibular joint, requiring evaluation by a Dentist finger (representing the lower trunk), when the thresh- or Oral Surgeon. In some there is neck pain. It is crit- old was compared between the at rest and the provoked ical to appreciate that the brachial plexus does take a measurement, the Pressure-Specified Sensory Device™ course across the thoracic inlet to enter the axilla be- was introduced for diagnosis (Lee et al. 2000). This ap- tween the clavicle (which isconcave atthislocation) and proach was refined to include measurements of one and the second rib; it does not travel between the clavicle two-point static and moving-touch, plus pinch and grip and the first rib. The upper trunk of the brachial plexus strength (Howard et al. 2003). A sensitivity of 100% and does travel beneath the anterior scalene muscle. There a specificity of 88% were obtained in the diagnosis of is a spectrum of congenital anomalies that course across severe brachial plexus compression using this approach. or through or under the brachial plexus that are respon- Treatment of brachial plexus compression should in- sible for the symptoms of the nerve compression, and clude stretching of the anterior scalene and strength- depending upon the location of the compression sites, ening of the upper trapezius, rhomboids, and serratus the symptoms will vary. These include: anterior muscles (Novak et al. 1995). This approach can relieve symptoms in 90% of patients. In those pa- • Cervical rib tients who fail to respond to non-operative methods, T • Fibrous Bands from C7 transverse process an exhaustive diagnostic approach must be undertaken • Extra Origins for Scalene Muscles to rule out causes that may give similar pain, prior to • Pre- or Post-fixed Brachial Plexus undertaking a surgical decompression of the plexus. • Intra-Plexus anomalous connections Additional diagnostic testing should include chest • Elevated position of Subclavian Artery X-ray, cervical and shoulder MRI, and evaluation of • Muscle of Albinus (scalenus minimus) peripheral nerve entrapments such as carpal and cubital • Fibrous edges of Scalene Muscles tunnel syndrome, since these entrapments, cervical • Anomalous vessels crossing Plexus disc disease and intrinsic shoulder pathology are the • Sibson’s Fascia crossing T1 nerve root commonest causes of these types of pain (Campbell et • Proximal junction of T1 to C8 al. 1991; Levin and Dellon 1992). Secondary compression of the cervical plexus by a The surgical treatment of brachial plexus compression tight or spasmodic anterior scalene muscle is the cause mustaccomplish a decompression of the brachialplexus of the facial pain, and this muscle pulling upon the from whichever structure or structures are causing the occiput is the source of the headache (Mackinnon and compression. Historically, just the scalenus anterior Dellon 1988). A winging component to the scapula is was resected (Mackinnon and Dellon 1988). In 1966, due to compression of the long thoracic nerve as it exits the transaxillary first rib resection was introduced, with between the medial and posterior scalene muscles, and the concept that the plexus was compressed between the this can be corrected by including a neurolysis of this first rib and the clavicle (Roos 1966). This is a difficult branch of the brachial plexus in the surgical approach approach, requiring wide retraction from the axilla in (Disa et al. 2001). order to reach the posterior border of the first rib. Com- 2478 Thoracic Surgery plications include burning pain in the distribution of the 9. Leffert RD (1992) Thoracic Outlet Syndromes. Hand Clinics 2nd or3rd intercostobrachialnerveduetostretch/traction 8:285–291 10. Levin LS, Dellon AL (1992) Pathology of the Shoulder as it injury, and injury to the subclavian artery, pneumoth- Relates to the Differential Diagnosis of Thoracic Outlet Com- orax, and injury to the C8 or T1 nerve roots, as they pression. J Reconstr Microsurg 8:313–317 cross the posterior border of the first rib. Due to per- 11. Mackinnon SE, Dellon AL (1988) Surgery of the Peripheral sistent upper trunk symptoms following transaxillary Nerve, 1st edn. Thieme, New York, pp 175–191 first rib resection, an anterior scalene resection often 12. Novak CB, Collins ED, Mackinnon S (1995) Outcome following Conservative Management of Thoracic Outlet Syndrome. J Hand had to be added as a secondary procedure. This gave Surg 20A:542–548 rise to the supra-clavicular surgical approach through 13. Roos D (1966) Transaxillary Approach to the First Rib to Relieve which the anterior (and medial) scalene muscles could Thoracic Outlet Syndrome. Ann Surg 163:354–358 be resected, a neurolysis of the brachial plexus could 14. Roos D, Wilbourn AJ (1990) Thoracic Outlet Syndrome is Un- derrated/Overdiagnosed. Arch Neurol 47:228–230 be done under direct vision, the major vessels could be 15. Sanders RJ (1991) Thoracic Outlet Syndrome: A Common Se- identified and protected, and a cervical or first rib could quelae of Neck Injuries. JB Lippincott Co, Philadelphia still be resected if necessary (Dellon 1993; Hempel et al. 16. Wilbourn A, Urschel HC (1984) Evidence for Conduction Delay in Thoracic Outlet Syndrome is Challenged. New Eng J Med 1996; Sanders 1991). The results reported by Hempel 310:1052–1053 et al in 1996 are worth noting: During a 28-year period, 637 patients underwent 770 supraclavicular first rib resections and scalenectomies for thoracic outlet syn- drome. Following surgery an excellent response was Thoracic Surgery achieved in 59%, good in 27%, fair in 13%, and poor in 1%. One lymphatic leakage and no brachial plexus Definition injuries resulted. Postoperative causalgia requiring sub- Thoracic surgery includes all thoracic surgical proce- sequent sympathectomy developed in two cases. No dures performed with lateral thoracotomy or median vascular or permanent phrenic nerve injuries occurred, sternotomy. and 12 patients (2%) required operative intervention  Postoperative Pain, Thoracic and Cardiac Surgery for recurrence. Sanders, in 1991, reported no difference in the outcome whether he resected the first rib, or did not resect it. The author’s preferred approach is a supraclavicular anterior scalenectomy and neurolysis Thought Suppression of the brachial plexus, preserving the first rib. During fifteen years with this approach, there has not been one Definition pneumothorax, or injury to the brachial plexus or major vessels. There have been two patients with transient The intentional act of excluding certain thoughts from phrenic nerve palsy. consciousness.  Psychology of Pain, Assessment of Cognitive Vari- References ables 1. Campbell JN, Naff N, Dellon AL (1991) Thoracic Outlet Syn- drome: A Neurosurgical Perspective. Neurosurg Clin N Am 2:227–234 Threat Appraisal 2. Cherington M, Cherington C (1992) Thoracic Outlet Syn- drome Reimbursement Patterns and Patient Profiles. Neurology 42:492–495 Definition 3. Dellon AL (1993) The Results of Supraclavicular Brachial Plexus Neurolysis (without First Rib Resection) in Management of Post- The judgment that a stressful event, such as pain, is Traumatic “Thoracic Outlet Syndrome”. J Reconstr Microsurg threatening. 9:11–17  Psychological Aspects of Pain in Women 4. Disa J, Wang B, Dellon AL (2001) Correction of Scapular Wing- ing by Neurolysis of the Long Thoracic Nerve. J Reconstr Mi- crosurg 17:79–84 5. Gilliatt RW, Le Quesne PM, Logue V et al. (1970) Wasting of the HandAssociatedwithaCervicalRib orBand. JNeurol Neurosurg Three-Way Scaling Models Psychiatry 33:615–619 6. Hempel GK, Shutze WP, Anderson JF et al. (1996) 770 Consec- utive Supraclavicular First Rib Resections for Thoracic Outlet Definition Syndrome. Ann Vasc Surg 10:456–463 7. Howard M, Lee C, Dellon AL (2003) Documentation of Brachial Three-way scaling models provide, in addition to the Plexus Compression in the Thoracic Inlet Utilizing Provocation group stimulus space, a subject weight space that pro- with Neurosensory and Motor Testing. J Reconstr Microsurg vides coordinates for the dimensions most salient to 19:303–312 each individual. 8. Lee GW, Massry DR, Kupfer DM et al. (2000) Documentation  of Brachial Plexus Compression in the Thoracic Inlet with Quan- Multidimensional Scaling and Cluster Analysis Ap- titative Sensory Testing. J Reconstr Microsurg 16:15–20 plication for Assessment of Pain Threshold Determination Protocols 2479

embedded in the measure. One must consider, for in- Threshold stance, in comparing two groups of people, whether a group difference in motor reaction time could be Definition large enough to produce different thresholds with this measure. Alternatively, and perhaps more likely, The threshold is the endpoint for the appearance of a is whether slower decision making in one group vs. given reaction or behavior. another (i.e. aged or patient groups) could account  Randall-Selitto Paw Pressure Test for slower responses, thus leading to higher thresh-  Statistical Decision Theory Application in Pain As- olds. sessment One of the common variants of this protocol uses a con- tact  thermode, and runs a series of trials to estimate thethresholdforinnocuousthermalsensation(warmand Threshold Determination Protocols cool), and then cold pain and heat pain. In the example provided in Figure 2 (Greenspan 2001), the thermode JOEL D. GREENSPAN wasplaced on the testsite (rightfoot) atan adapting tem- Department of Biomedical Sciences, University of perature of 32˚C. Then, without warning to the subject, Maryland Dental School, Baltimore, MD, USA the temperature was decreased (cool or cold pain trials) [email protected] or increased (warm or heat pain trials) at a fixed rate of temperature change (1.0˚C/s). The subject depressed a Synonyms button when she felt the particular sensation for which Quantitative Sensory Testing (QST). Although not she was instructed to attend. These trials are repeated strictly synonymous, QST refers to a particular set of typically 3–4 times for each sensory modality, and an threshold determination protocols used for both pain average value is calculated for threshold. and innocuous sensory evaluation. A variant of this protocol was referred to as the  Marstock method, and used oscillating tempera- Definition tures between warm and cool or heat and cold pain thresholds (Fruhstorfer et al. 1976). While somewhat Threshold determination protocols are those psy- faster than a protocol that separately evaluated warm, chophysical procedures used to estimate perceptual cool, heat pain and cold pain thresholds, the Marstock threshold. These protocols (of which there are several) method relied on the subject recognizing the change in are defined by the rules by which stimuli are applied, the temperature direction each time, and knowing which ways that responses are measured, and how the entire sensation to attend to at any point in time. This may be sequence of events is orchestrated. confusing for a patient with  paresthesia, or those who have completely lost the ability to feel some sensory Characteristics qualities. There are several protocols in the literature that estimate Almost all other pain threshold protocols use fixed dura- pain threshold. To a large extent, these protocols are the tion stimuli of a prescribed intensity, and do not rely on T sameasthoseused to estimatethethreshold of other sen- the subject’s reaction time (see Fig 1, bottom). The most sory systems. These protocols have been developed and common protocol of this type is a Staircase protocol, or modified over the last 150 years, resulting in many vari- one of its variants, including the Method of Levels. In ations (Boring 1942). thistypeofmethod,aseriesofstimulusintensitiesispre- One important distinction is between those protocols scribed with a few simple rules. After a single stimulus that depend upon the subject’s reaction time (RT), and is applied, the subject reports whether it was painful or those that do not (Yarnitsky 1997). The most commonly not. If it was not painful, the next stimulus is more in- used RT-dependentprotocol is referred to as the Method tense. If it was painful, the next stimulus is less intense. of Limits. Within this protocol, the stimulus intensity Stimuliareappliedaccordingtotheserulesuntilaprede- (i.e. temperature with a thermal probe or force with fined endpoint is reached. That endpoint can be defined a pressure  algometer) is gradually increased until in terms of the number of “response reversals” (i.e. go- the point at which the subject indicates he feels pain, ing from “painful” to “non painful”, or vice versa, from typically by pushing a button. The stimulus level at the one trial to the next). Variations of this protocol include time of that report is taken as the pain threshold (Fig. 1, the way in which stimulus intensity is changed from trial top). One can also use this same approach and have the to trial. For instance, it is common to start the protocol subject indicate the limits of his tolerance. with relatively large changes (or “steps”) in stimulus in- A major reason for its wide use is the simplicity of tensity from trial to trial (such as 2–4˚C steps to derive this protocol, particularly in the clinical environ- heat or cold pain), and reduce step size as the session ment. However, it has some distinct disadvantages, progresses. The initial temperature is typically chosen including the obvious confound of a motor response to be well below pain threshold, so subsequent stimuli 2480 Threshold Determination Protocols

Threshold Determination Proto- cols, Figure 1 Representation of a reaction time-dependent (top) and a reaction time independent (bottom) protocol. Top: Stimulus intensity increases until the subject indicates (s) he feels pain (or another specified percept), at which time the stimulus is returned to its baseline level. The stimulus intensity at the time of the report is taken as an estimate of threshold. This process is repeated, and the threshold estimates averaged across trials. Bottom: A prescribed stimulus is presented, and the subject is instructed to provide a response at the end of the stimulus (i.e. “painful” or “not painful”). Depending upon the response, subsequent stimuli are of either greater or lesser intensity. See text for further details. will be of larger intensity, until the subject reports that the protocol continues using that step size for several re- one of the stimuli is painful. At that point, the next stim- sponse reversals. In this case, the threshold is calculated ulus is of a lower intensity, but thechange in temperature as an average of the last few (typically 4–6) response re- will be less (for instance, half of the step size used to that versal temperatures. point). Once a stimulus intensity is reached that is not A simpler variant of this type of protocol is to use a se- painful, the next stimulus will be of a greater intensity, ries of stimuli in ascending intensity, until a stimulus is but will be yet a smaller step size. In this manner, the given that the subject reports as painful. This protocol stimuli are “titrated” to reach the intensity closest to the is something like the Method of Limits (in terms of in- painful/non-painful level, ultimately at the smallest step creasing stimulus intensity), but uses discrete stimulus size (resolution) desired. For the Method of Levels, the trials, to make it a reaction time-independent protocol. stepsizesaregraduallyreduced,andtheprotocoliscom- The threshold would be estimated as the stimulus inten- pletewhentheminimallydesiredstepsizeisachieved.In sity between the first painful stimulus and the immedi- this case, the threshold is the average of the temperature ately preceding one. This Ascending Method of Lim- atthelasttworesponsereversals.FortheStaircaseproto- its would be repeated several times, and threshold esti- col, the step sizes reduce quickly to a minimal value, and matesaveraged.Aprotocolofthistypehasbeensuccess- Threshold Determination Protocols 2481

Threshold Determination Protocols, Figure 2 An example of a threshold data set gathered using the Method of Limits protocol. The bars represent the temperature reached for each trial at the time the subject pressed a button to indicate she felt a particular perception. The particular sensation for any given set of trials is indicated at the bottom of the graph. The threshold for each sensory percept is calculated as the average of each trial, and indicated at the top of the graph (Adapted from data presented in Greenspan 2001). fully used for mechanical pain thresholds (Greenspan and McGillis 1991) and heat pain thresholds (Dyck et al. 1996). One problem with these protocols is the subjects’ pre- dictability of the stimulus sequence, particularly after some experience with it. One way to thwart such pre- Threshold Determination Protocols, Figure 3 Data from two multiple- dictability is to include some “out of sequence” stimulus staircase sessions using thermal stimuli. Three different staircases were intensities at random times, which are irrelevant to the prescribed: one for cool sensation, one for slight heat pain sensation, and course of the staircase. Another way is to use a Multi- one for moderate heat pain sensation. Each filled symbol represents a single ple Staircase protocol. For this protocol, one starts two temperature presentation (a trial). After each stimulus was presented, the subject chose a descriptor that best represented his sensation from a list of or more staircases, each operating by the same rules de- thermal and pain terms. For each staircase, successive stimuli were more scribed above. However, from trial to trial, the stimu- intense until the criterion response was elicited. Then, subsequent stimuli lus may be drawn from any of the staircases, determined were progressively less intense, until a response other than the criterion randomly. Thus, at the end of the protocol, one has two response was elicited. Thus, the stimulus at which the subject’s response changed with respect to the criterion response produced a reversal of the or more estimates of pain threshold – one derived from staircase. The trials producing such staircase reversals are marked by the each staircase – and the stimulus sequence was unpre- open symbols surrounding the filled symbols. Each staircase was continued T dictable on a trial by trail basis. Another variation of the until six reversals occurred. The dotted lines denote the calculated thresh- old for a given staircase, based on the average of its last four reversals. multiple staircase protocol allows one to derive thresh- On any given trial, a random process selected one of the three staircase olds for more than just the pain threshold. If the subject algorithms to determine the temperature, thus preventing any prediction of is instructed to report from a list of qualitative descrip- the stimulus sequence. The adapting temperature was 34.0˚C. (Reprinted tors (i.e. “warm”, “hot”, “slight pain”, “moderate pain”, with permission from Taylor et al. 1993; http://www.tandf.co.uk/journals). etc.), one can prescribe a staircase to titrate to any one of the qualitative percepts. Gracely et al. (1988) used this protocol to derive thresholds for “slight pain”, “moder- In principle, one should be able to compare directly ate pain”, and “intense pain”, in a single test session, threshold data gathered at different times, and by dif- with heat stimuli. Taylor et al. (1993) and Greenspan et ferent investigators, using the same protocol. Such al. (1993) used a multiple staircase protocol to derive comparisons are tenuous, due to the fact that varia- thresholds for “cool”; “slight heat pain” and “moder- tions in protocol may systematically alter the resulting ate heat pain” (see Fig. 3). However, the Greenspan et threshold values. Differences in stimulus area, rate of al. report revealed that mixing of cool and heat stimuli stimulus change, inter-stimulus interval, and precise increased the incidence of paradoxical heat sensations, body site tested can significantly alter pain thresholds. rendering cool threshold estimates problematic in some Furthermore, situational factors such as the subject’s instances. Thus, it may be preferable to restrict multiple general comfort, or the instructions to the subject, can staircases (or any other threshold protocol) to either de- affect threshold values. It is for these reasons that com- tection or pain thresholds, within a single modality, for parisons of threshold values are better made within a any single block of trials. given study, rather than across studies (Shy et al. 2003). 2482 Thromboembolism

References Thromboxane 1. Boring EG (1942) Sensation and Perception in the History of Experimental Psychology. Appleton-Century-Crofts, New York 2. Dyck PJ, Zimmerman IR, Johnson DM et al. (1996) A Stan- Definition dard Test of Heat-Pain Responses using CASE IV. J.Neurol.Sci 136:54–63 Thromboxanes are arachidonic acid derived molecules 3. Fruhstorfer H, Lindblom U, Schmidt WG (1976) Method for that are involved in platelet aggregation and blood clot- Quantitative Estimation of Thermal Thresholds in Patients. J Neurol Neurosurg Psychiatry 39:1071–1075 ting. 4. Gracely RH, Lota L, Walter DJ et al. (1988) A Multiple Ran-  COX-1 and COX-2 in Pain dom Staircase Method of Psychophysical Pain Assessment. Pain  NSAIDs, Adverse Effects 32:55–63 5. Greenspan JD (2001) Quantitative Assessment of Neuropathic Pain. Curr Pain Headache Rep 5:107–113 6. Greenspan JD, McGillis SLB (1991) Stimulus Features Rele- vant to the Perception of Sharpness and Mechanically Evoked Thromboxane A2 Cutaneous Pain. Somatosens Mot Res 8:137–147 7. Greenspan JD, Taylor DJ, McGillis SLB (1993) Body Site Vari- ation of Cool Perception Thresholds, with Observations on Para- Definition doxical Heat. Somatosens Mot Res 10:467–474 8. Shy ME, Frohman EM, So YT et al. (2003) Quantitative Sensory Thromboxane A2 is a prostaglandin-like material that is Testing: Report of the Therapeutics and Technology Assessment synthesized mainly by a COX–1–dependent process in Subcommittee of the American Academy of Neurology. Neurol- ogy 60:898–904 activatedplatelets.ThromboxaneA2promotesvasocon- 9. Taylor DJ, McGillis SLB, Greenspan JD (1993) Body Site Vari- striction and aggregation of platelets, thereby initiating ation of Heat Pain Sensitivity. Somatosens Mot Res 10:455–466 the clotting of blood. 10. Yarnitsky D (1997) Quantitative Sensory Testing. Muscle Nerve  NSAIDs and their Indications 20:198–204

Tic and Cranial Neuralgias

Thromboembolism 1 2 Z. HARRY RAPPAPORT ,MARSHALL DEVOR 1Department of Neurosurgery, Rabin Medical Center, Definition Tel-Aviv University, Petah Tikva, Israel 2Institute of Life Sciences and Center for Research A thromboembolism is a blood clot (thrombus) formed on Pain, Hebrew University of Jerusalem, Jerusalem, in a blood vessel after surgery, which is transported as Israel an embolus to the lungs or brain to cause an infarct. [email protected], [email protected]  Postoperative Pain, Acute Pain Team Synonyms Cranial Neuralgias Neuralgia of Cranial Nerve V; trigeminal neuralgia; tic Thrombosis douloureux; tic doloreux Neuralgia of Cranial Nerve IX with or without Cranial Nerve X; glossopharyngeal neuralgia; vagoglossopha- Definition ryngeal neuralgia; Neuralgia of Cranial Nerve VII; Thrombosis is the formation of clots inside blood ves- geniculate neuralgia sels.  NSAIDs and their Indications Definition Cranial nerve neuralgia refers to a clinical pain symp- tom complex that consists of recurrent, intermittent, often paroxysmal pain felt in the head, in the distri- bution of a specific cranial nerve. By far the most Thrombotic Event commonly encountered cranial nerve neuralgia is that of the trigeminal nerve and root. This is trigeminal neuralgia (tic douloureux). Neuralgias of the vago- Definition glossopharyngeal nerves and the nervus intermedius Thrombotic Event refers to the formation of blood clots branch of the facial nerve are much rarer. Cranial nerve in blood vessels e.g. coronary or cerebral arteries. neuralgias are severely painful, but non life-threatening  NSAIDs, Adverse Effects conditions. Tic and Cranial Neuralgias 2483

Characteristics giving the impression of a prolonged attack over hours. Clinical Phenomenology Typically, pain attacks come in clusters separated by remissions of days to months, and sometimes even Trigeminal neuralgia is unique among cephalic-facial years (Rasmussen (1990). Following an attack the trig- pain syndromes, both for its dramatic symptomatology ger area remains relatively refractory to further pain as for its susceptibility to both drug and interventional inducing stimuli for up to 2 minutes (Kugelberg and therapy. The incidence is approximately 4 new cases Lindblom 1959). Routine sensory examination of the per 100,000 population/year. It is much more common face does not usually reveal any changes, but quanti- in the elderly than in young patients. There is no definite tative sensory testing may reveal elevated tactile and sex predisposition. Intense, intermittent paroxysms of thermal detection thresholds in the area surrounding and pain in the distribution of the trigeminal branches are including the trigger point (Nurmikko 1991). Trigemi- followed by variable pain-free periods. The pain is uni- nal neuralgia is idiopathic; there is rarely any obvious lateral and does not cross the midline of the face. There precipitating injury or disease. Prominent hypoes- is usually a distinct trigger point, most commonly in thesia in the presence of typical trigeminal neuralgia the perinasal or perioral area, but sometimes within the symptoms implies the presence of a paratrigeminal oral cavity. When the trigger point is stimulated, after space occupying lesion or multiple sclerosis. This is a short latency period, the painful paroxysm begins sometimes termed atypical trigeminal neuralgia. (Fig. 1). Pain may radiate from the trigger area along The symptomatology of glossopharyngeal neuralgia the appropriate trigeminal division, sometimes crossing is similar to that of trigeminal neuralgia, but pain is into adjacent divisions. Trigger stimuli are usually quite felt in the distributions of the ninth (glossopharyn- weak, such as light touch, chewing, talking movement geal) and/or tenth (vagus) cranial nerves (Rushton et or a puff of wind. Paroxysms may also arise sponta- al. 1981).  Pain paroxysms are usually triggered dur- neously. Noxious stimulation of the trigger points is ing swallowing, talking, or chewing, with the trigger usually ineffective (Kugelberg and Lindblom 1959). point located unilaterally at the base of the tongue, The pain onset is usually sudden, and has an electric tonsillar region, or in the ear. Concomitant vagal au- shock-like quality. A series of attacks, building to a tonomic involvement probably accounts for episodes crescendo, is common. Patients describe the pain as of syncope and bradycardia that may accompany pain “shooting”, “electric”, or “cutting” in quality. While attacks. In more severe cases, prolonged asystole may the paroxysms tend to be short, in the order of seconds be life threatening. The disease is equally distributed or occasionally minutes, they can run into each other between the sexes and is most frequently seen between the fifth and seventh decades of life, with an incidence of 0.8 cases/100,000/year. It is occasionally bilateral in presentation. Pain tends to be less severe than trigeminal neuralgia, and often more steady and burning in quality (Katusic et al. 1991). Geniculate neuralgia involves the sensory distribution of the seventh cranial nerve (facial nerve) via the nervus T intermedius (of Wrisberg). The painful attacks, which are sharp and stabbing, are centered within the ear canal (Pulec 2002). A dull background pain may persist for several hours after an attack. Affected patients tend to beyoungerthanintrigeminalandglossopharyngealneu- ralgia. When seen together with hemifacial spasm, the term“ticconvulsive”hasbeenused(YehandTew1984).

Pathophysiology Medical and surgical experience in treating tic, com- bined with pathological findings and laboratory experi- ments using animal models, sheds light on the etiology of pain paroxysms in the cranial nerve neuralgias. Dur- ing exploration of the cerebello-pontine angle on the side of the pain, vascular compression of the appropriate nerve root is usually observed (Fig. 2). Following de- compression, the patients are relieved of their pain in a high percentage of cases (Yeh and Tew 1984; Sindou et Tic and Cranial Neuralgias, Figure 1 A patient winces during a right- al. 2002; Patel et al. 2002). Ultrastructural examination sided trigeminal neuralgia attack. of post-mortem specimens, and cranial nerve biopsies 2484 Tic and Cranial Neuralgias

Tic and Cranial Neuralgias, Figure 2 A photomicrograph of a compressed trigeminal root (short arrow) and the compressing blood vessel (long arrow), taken during microvascular decompression surgery in trigeminal neuralgia. Note the discoloration of the root at the compression site. taken during surgical procedures, show extensive patho- phenytoin. Barbiturates are not effective, presumably logical change in the cranial nerve root and ganglion becausetheyactsynapticallyratherthanas  membrane (Devor et al. 2002a; Devor et al. 2002b). Disordering stabilizers. The effectiveness of drug therapy declines and loss of myelin is seen in the area compressed by the over time in nearly one half of cases. When drug therapy vessel loop, as are signs of axonal sprouting and regions no longer controls the pain paroxysms, or its side effects of close membrane contact between adjacent denuded impair quality of life, interventional procedures may be axons. The later observation is a likely anatomical sub- considered (Rappaport 1996). Peripheral nerve blocks strate of ephaptic (electrical, non-synaptic) coupling or neurectomies have only a short-term effect. Most between axons. These types of structural change can elderly patients undergo percutaneous partial damage give rise to ectopic pacemaker sites, and the genera- to the trigeminal root and ganglion using radiofre- tion of abnormal impulse discharge. Moreover, they quency coagulation, retro-Gasserian glycerol injection facilitate neuron-to-neuron spread of electrical activity or balloon compression. The initial success rate is in through the injured cranial nerve root and its sensory the 80 % range, with recurrence rates of up to 30 % at 1 ganglion, by means of neurophysiological mechanisms year and up to 45 % at 5 years. These procedures entail such as  ephaptic coupling and crossed afterdischarge various degrees of facial hypoesthesia. Their efficacy (Rappaport and Devor 1994). The generation of self- is probably due to lessened triggering and reduction sustaining discharge in the root and ganglion following of trigeminal ganglion neuron populations, and hence peripheral triggering, and the rapid spread of this activ- reduction of the critical mass of electrical activity re- ity, is thought to cause paroxysms of pain. This is the quired for pain ignition. Radiofrequency rhizolysis of  “ignition hypothesis” of trigeminal neuralgia (Rap- the glossopharyngeal nerve is also effective for ninth paport and Devor 1994). Other properties of cranial nerve neuralgia; however, the procedure is technically nerve neuralgias, such as post-paroxysm refractori- more demanding. ness and pain suppression by membrane stabilizing For patients who can tolerate the surgery, open exposure anticonvulsants, are consistent with this mechanism of the posterior fossa via a retromastoid craniotomy, and (Rappaport and Devor 1994). Central changes in sig-  microvascular decompression of the neural complex, nal processing within the trigeminal brainstem have optionally combined with partial rhizolysis, is the pre- also been proposed as causes of tic pain (Fromm and ferred interventional procedure for allcranial nerve neu- Sessle–1991). ralgias.Microvasculardecompressionhastheadvantage of treating the root cause of the symptoms without de- Treatment stroying neural tissue and superimposing hypoesthesia. The hallmark of cranial nerve neuralgias is their re- The low morbidity and mortality of this procedure (less sponse to specific anticonvulsant medications, notably than 4 %), and its impressive efficacy at relieving pain carbamazepine and gabapentin, and to a lesser extent with only modest rates of recurrence (80 % still with sig- Timolol 2485 nificant pain relief at 5 year follow-up) makes microvas-  Trigeminal Neuralgia cular decompression the surgical treatment of choice, at  Trigeminal Neuralgia, Diagnosis and Treatment least in younger patients (Rappaport 1996).  Trigeminal Neuralgia, Etiology, Pathogenesis and Management Acknowledgements We wish to thank Prof. Yair Sharav of the Hebrew Uni- versitySchoolofDentistryforprovidinguswiththepho- tograph of a patient during a trigeminal neuralgia parox- Time Constant ysm used in Figure 1. Definition References 1. Devor M, Govrin-Lippmann R, Rappaport ZH (2002a) Mech- For a variable that is an exponential function of time anism of Trigeminal Neuralgia: An Ultrastructural Analysis of Trigeminal Root Specimens Obtained during Microvascular De- compression Surgery. J Neurosurg 96:532–543 2. Devor M, Govrin-Lippmann R, Rappaport ZH, Tasker RR, Dostrovsky JO (2002b) Cranial Root Injury in Glossopharyn- τ geal Neuralgia: Electron Microscopic Observations. J Neurosurg the time constant ( ) is the time after which the variable 96:603–606 (x) has decreased by 1/e or increased by e. 3. Fromm GH, Sessle BJ (1991) Trigeminal Neuralgia: Current  Mechano-Insensitive C-Fibres, Biophysics Concepts Regarding Pathogenesis and Treatment. Butterworth- Heinemann, Boston, pp 1-230 4. Katusic S, Williams DB, Beard CM, Bergstralh EJ, Kurland LT (1991) Epidemiology and Clinical Features of Idiopathic Trigem- inal Neuralgia and Glossopharyngeal Neuralgia Similarities and Time-Contingent Medication Differences, Rochester, Minnesota, 1945–1984. Neuroepidemi- ology 10:276–281  5. Kugelberg E, Lindblom U (1959) The Mechanism of the Pain in Time-Locked Medication Trigeminal Neuralgia. J Neurol Neurosurg Psychiat 22:36–43 6. Nurmikko TJ (1991) Altered Cutaneous Sensation in Trigeminal Neuralgia. Arch Neurol 48:523–527 7. Patel A, Kassam A, Horowitz M, Chang YF (2002) Microvas- Time-Locked Medication cular Decompression in the Management of Glossopharyngeal Neuralgia: Analysis of 217 Cases. Neurosurgery 50:705–710 8. Pulec JL (2002) Geniculate Neuralgia: Long-Term Results of Synonyms Surgical Treatment. Ear Nose Throat J 81:30–33 9. Rappaport ZH (1996) The Choice of Therapy in Medically In- Time-Contingent Medication tractable Trigeminal Neuralgia. Isr J Med Sci 32:1232–1234 10. Rappaport ZH, Devor M (1994) Trigeminal Neuralgia: The Role Definition of Self-Sustaining Discharge in the Trigeminal Ganglion. Pain 56:127–138 Time-locked medication refers to medication intake not 11. Rasmussen P (1990) Facial Pain: A Prospective Study of 1052 on an as needed (prn) schedule but at fixed points in time Patients with a View of: Character of the Attacks, Onset, Course, and Character of Pain. Acta Neurochir 107:121–128 to avoid maladaptive learning processes. T  12. Rushton JG, Stevens JC, Miller RH (1981) Glossopharyngeal Operant Treatment of Chronic Pain (Vagoglossopharyngeal) Neuralgia: A Study of 217 Cases. Arch Neurol 38:201–205 13. Sindou M, Howeidy T, Acevedo G (2002) Anatomical Obser- vations during Microvascular Decompression for Idiopathic Timing Trigeminal Neuralgia (with Correlations between Topography of Pain and Site of the Neurovascular Conflict). Prospective Study in a Series of 579 Patients. Acta Neurochir 144:1–12 Definition 14. Tyler-Kabara EC, Kassam AB, Horowitz MH, Urgo L, Hadji- panayis C, Levy EI, Chang YF (2002) Predictors of Outcome in In the context of pre-emptive analgesia: an analgesic Surgically Managed Patients with Typical and Atypical Trigem- treatment can be initiated (or „timed“ to start) before inal Neuralgia: Comparison of Results following Microvascular Decompression. J Neurosurg 96:527–531 or after the surgical injury.  15. Yeh HS, Tew JM Jr (1984) Tic Convulsive, the Combination of Postoperative Pain, Pre-Emptive or Preventive Anal- Geniculate Neuralgia and Hemifacial Spasm Relieved by Vas- gesia cular Decompression. Neurology 34:682–68

Tic Douloureux Timolol Definition  Tic and Cranial Neuralgias  Trigeminal, Glossopharyngeal, and Geniculate Neu- A beta-blocker. ralgias  Migraine, Preventive Therapy 2486 Tinel Sign

estimates of the recovery times of peripheral nerves, and Tinel Sign ranged from 1–3 mm/per day (Sunderland 1968). TURO J. NURMIKKO Not long after Tinel and Hoffman published their first Department of NeurologicalScience and Pain Research papers, there were reports by several surgeons that the Institute, University of Liverpool, Liverpool, UK signfailedtoindicateaccuratelywhetherornotrecovery [email protected] of the injured nerve wastaking place. Reportsof patients with a positive Tinel sign, who at operation were found to have total interruption of the nerve with no chance of Synonyms recovery, were published. It appears that the essential requirement for the sign to be positive – that it was pro- Tinel’s sign; Hoffman-Tinel sign; sign of formication gressing – was overlooked by many. Nevertheless, more criticism toward the sign was generated by observations Definition of good neural recovery in patients in whom the Tinel Tingling or sensation of pins and needles elicited by an signwasmissing(Napier1949;DavidandChung2004), examiner tapping over a nerve. Tingling must be felt in and the test fell into disfavor. Later, a few investigators the territory supplied by the nerve. published relatively large case series and concluded that it is, when used critically, of moderate use as a rough guide of nerve recovery (Napier 1949; Nathan and Ren- Characteristics nie 1946) There are today other more advanced meth- The Tinel sign is a simple clinical test to identify local ods for assessment of such recovery, and the sign is to nerve damage or map the progress of nerve regeneration be regarded more as a curiosity than a valid clinical tool. following nerve injury. It was championed in the 1910s Despite this, it is always introduced to medical students by two neuroscientists independently of each other, Dr. and regularly appears in surgical and neurological text- Jules Tinel (1879 – 1952), a French Neurologist, and books. Paul Hoffman (1884 – 1962), a German Neurophysi- The basis for the test lies in increased excitability of the ologist, but there are earlier descriptions of the sign in recovering nerve fibers. Following injury, nerve fibers medical literature. The phenomenon was probably well begin to grow sprouts from the proximal stump. These known to the medical community before their reports. sprouts are far more sensitive to mechanical stimuli than Tinel and Hoffman are, however, credited for highlight- are mature nerve fibers in intact nerves. As the sprouts ing the clinical potential of the sign and giving it a mea- go longer, the most distant point of mechanical sensitiv- sure of scientific validity (Wilkins et al. 1971). ity moves further away from the injury.  Myelin break- The Tinel sign is a tingling perceived by a patient with age and restoration, and recovery of support structures nerveinjury when theexaminertapsoverthetrunkofthe of the nerve trunk, also have an impact on the general nerve. Tingling is felt in the skin supplied by the nerve, excitability of the recovering nerve. In the part of the does not change on repetition, and outlasts the stimu- nerve in which full or near-full recovery of fibers has lus by no more than a few seconds. Tinel and Hoffman taken place, the nerve trunk loses its sensitivity to per- considered this to signal the presence of regenerating cussion.  axons, which start to sprout from the proximal part of Tinel, and later advocates of his method, stressed the nerve after injury. The further the recovery advances, that tapping should produce tingling, not pain in the the further away from the site of injury the Tinel sign can reference area. Tinel did acknowledge that at times be elicited. In this way, the successful progress of nerve mechanical compression of the site of injury could recovery can be tracked. cause pain, prominent on the site of compression, In its classical form, the test is carried out by applying with less intense pain referred to the territory of the repeated percussions by one’s extended finger over the nerve. To Tinel, the natural explanation for a stationary presumed course of the nerve, initially well below the sign was that nerve degeneration did not take place, expectedtarget,andcontinuedupwardsuntilthefirsttin- and that the regenerating nerves grew aimlessly into gling sensation is elicited. The site where this happens is a bundle of sprouts, forming a  neuroma.Neuromas the maximum distance over which the nerve fibers have are known for their excessive mechanical sensitivity. regenerated. In order to prevent false results from vibra- Inevitably, the sign was soon adopted for diagnosing tions induced on the skin, the examiner places his free neuromas, with no evidence that it provides more infor- hand between thepercussing finger and thesiteof injury. mation than careful manual palpation or compression. Intheearlyyearsofitspopularity,thesignwasusedtoes- It has been suggested that a neuroma can be distin- timate the rate of recovery of the nerve following injury. guished from other tender structures at the operation Large case series were published, mostly involving pa- site by using a series of light weight percussion tools tients with gun shot wounds who had undergone surgery (Tucker and Nancarrow 2000), but this method is not for their injury. At the time these were the best available in common use. There are sophisticated electrophys- TNS 2487 iological and neuroimaging methods that can be used instead. Tissue Fatigue In the 1950s, Phalen and co-workers reported that they could frequently elicit the Tinel sign in patients with Definition  carpal tunnel syndrome and added the test to their Tissue fatigue refers to a decline in the load-bearing ca- other diagnostic criteria (Phalen et al. 1950). In carpal pacity of tissue in response to an applied load. This phe- tunnel syndrome, the median nerve is under constant nomenon is reversible provided that there is sufficient compression, imposing increasing structural damage time for recovery. on nerve fibers. Axonal degeneration and regeneration  Ergonomic Counseling take place concurrently, and with varying levels of demyelination and remyelination present, the nerve becomes excessively sensitive to mechanical stimuli. However, several studies have been published that show TLIF convincingly that the Tinel sign has little to offer for differential diagnosis. It is too crude a test for accurate differentiation between patients with carpal tunnel syn- Synonyms drome from those with other peripheral nerve diseases, Transforaminal interbody fusion or even healthy people (D’Arcy et al. 2000). The significance of the Tinel sign has faded with time, Definition and these days it remains more a curiosity than a serious Graft/cages placed between the vertebral bodies by pos- clinical tool. It is still used out of its original context in terior approach through the neural foramina without re- pain research – more as a “neuroma sign”, rather than tracting the thecal sac. the sign of a recovering nerve than it was used for in the  Spinal Fusion for Chronic Back Pain early part of the 20th century.  Neuroma Pain  Peripheral Neuropathic Pain  Ulceration, Prevention by Nerve Decompression TMD References  Temporomandibular Disorder 1. D’Arcy CA, McGee S (2000) Does this Patient have Carpal Tun- nel Syndrome? JAMA 283:3110–3117 2. Dellon AL (1984) Tinel or not Tinel. J Hand Surg 9:216 3. David EN, Chung KC (2004) The Tinel Sign: A Historical Per- spective. Plast Recontr Surg 114:494–499 TMS 4. Moldaver J (1978) Tinel’s Sign. J Bone Joint Surg 60-A:412–413 5. Napier JR (1949) The Significance of Tinel’s Sign in Peripheral Nerve Injuries. Brain 72:63–82  Transcranial Magnetic Stimulation 6. Nathan PW, Rennie AM (1946) Value of Tinel’s Sign. T Lancet I:610–611 7. Phalen GS, Gardner WJ, LaLonde AA (1950) Neuropathy of the Median Nerve Due to Compression beneath the Transverse Carpal Ligament. J Bone Joint Surg 32A:109–112 TMJD 8. Sunderland S (1968) Nerves and Nerve Injuries. E&S Living- stone, Edinburgh 9. Tucker SC and Nancarrow JD (2000) Objective Assessment  Temporomandibular Joint Disorders of Post-Traumatic Nerve Repairs and Neuromas. Br J Plastic Surg 53:694–696 10. Wilkins RH, Brody IA (1971) Neurological Classics XXXIV. Tinel’s Sign. 24:573–575 11. Yarnitsky D, Ochoa JL (1991) The Sign of Tinel can be mediated TNF Alpha(α) either by Myelinated or Unmyelinated Primary Afferents. Muscle Nerve 14: 379–380  Tumor Necrosis Factor Alpha(α)

Tinnitus TNS Definition A ringing sensation in one or both ears.  Transcutaneous Electrical Nerve Stimulation Out-  NSAIDs, Adverse Effects comes 2488 Tolerance

 Central Pain, Human Studies of Physiology Tolerance  Thalamic Bursting Activity, Chronic Pain

Definition Tolerance refers to diminishing susceptibility to the ef- fects of a drug with continued use. The phenomenon of Tonic Rebalance tolerance is characteristic of opioid analgesics. The de- velopmentoftolerancetotheanalgesiceffectsoftheopi- Definition oidsmeansthatwithcontinuedopioiduse,progressively Tonic rebalance is a spontaneous, physiological process higher doses may be required to maintain the same anal- bywhichthesystemtriestorestoresymmetryatthelevel gesic effect. Tolerancealso developsto the nonanalgesic of the vestibular nuclei in the acute phase after a vestibu- side effects of opioids, including respiratory depression, lar crisis. The process occurs independently of the pa- nausea, and sedation. The development of tolerance to tient’s activities. these effects is desirable as it permits dose titration.   Coordination Exercises in the Treatment of Cervical Cancer Pain Management, Opioid Side Effects, Un- Dizziness common Side Effects  CRPS, Evidence-Based Treatment  Opiates During Development  Opioids and Inflammatory Pain Toothache  Opioids in the Periphery and Analgesia  Opioid Receptors  Opioid Responsiveness in Cancer Pain Management  DentalPain, Etiology, Pathogenesisand Management  Opioid Therapy in Cancer Patients with Substance Abuse Disorders, Management  Postoperative Pain, Opioids  Purine Receptor Targets in the Treatment of Neuro- Top-Down Control of Pain pathic Pain  Stimulation-Produced Analgesia Definition Neural pathways descending from higher brain struc- tures to lower brain structures modulate ascending pain Tolerance Thresholds signals.  Descending Modulation and Persistent Pain

 Pain in Humans, Thresholds Topical Drug Therapy Tolosa-Hunt Syndrome CHARLES NG Musculoskeletal Medicine Specialist, Australasian Faculty of Musculoskeletal Medicine, Auckland, New Definition Zealand Also called:“painfulophthalmoplegia“:avariablecom- [email protected] binationofperiorbitalpain,ipsilateraloculomotornerve palsies, oculosympathetic palsy and trigeminal sensory Definition loss. Topical drug therapy is the application of drugs to the  Headache due to Dissection skin over an area of pain. The drug penetrates the skin to act on the underlying painfultissues or thenerves than innervate them.

Tonic Firing Mode Characteristics The three main groups of topical medications used in Definition treating pain are topical NSAIDs (nonsteroidal anti- A pattern of spontaneous action potential firing demon- inflammatory drugs), topical local anaesthetics and strated by thalamic neurons, in which no clear pattern topical capsaicin. These drugs may be formulated as a of interspike intervals exists. cream, gel, paste or patch. Topical Drug Therapy 2489

Topical NSAIDs (nonsteroidal anti-inflammatory drugs) Topical Local Anaesthetics Mechanisms of Action Mechanisms of Action Topical NSAIDs have a peripheral action on soft tissue, Local anaesthetics act through the blockade of sodium inhibitingprostaglandinsynthesis,inhibitingthelipoxy- channels in sensory afferent neurons. Thereby, topical genase pathway and inhibiting excitatory amino acids. application reduces ectopic discharge in superficial They have effects on G protein-mediated signal trans- somatic nerves that are stimulated in neuropathic pain duction (Galer 2001). They also reduce the neurogenic states and acute injuries (Galer 2001). inflammatory response. Evidence shows that therapeutic concentrations are Applications and Efficacy achieved in soft tissues (Vaile et al. 1998). These tissues Studies support the efficacy of topical lidocaine, in can act as a drug reservoir, and thus maintain tissue either the Lidoderm patch or gel formulation, for re- and plasma concentration after application of the drug lieving pain in chronic  postherpetic neuralgia and for has ceased. Systemic redistribution of NSAIDs results mechanical  allodynia (Galer 2001, Sawynok 2003). in measurable plasma levels. However, plasma, mus- There is anecdotal evidence that topical lidocaine may cle and synovial fluid concentrations have been found beusefulfordiabeticandotherperipheral neuropathic to be lower than in subcutaneous fat and soft tissue, pains (Galer 2001). and are possibly subtherapeutic. Consequently, topical Topical application of EMLA (eutectic mixture of lo- NSAIDs are more effective for soft tissue complaints cal anaesthetics, 2.5% lidocaine and 2.5% prilocaine) than arthropathies. reduces acute pain associated with invasive procedures such as venipuncture (Galer 2001). It also reduces chronic pain in postherpetic neuralgia and chronic Applications and Efficacy post-surgical pain (Towlerton and Rice 2003). Topical NSAIDs are most effective for soft tissue Topical tetracaine provides effective anaesthesia for complaints. Evidence supports the use of ketorolac, endotracheal, ocular and invasive skin procedures flurbiprofen and niflumic acid in acute ankle sprain. (Galer 2001). Topical cocaine provides effective anaes- Indomethacin and piroxicam are effective in sprains thesia for nasal mucosa. and tendinitis. Naproxen and felbinac are effective A combination of a low dose of morphine and lidocaine in a variety of soft tissue injuries (Vaile et al. 1998). resultsin analgesic synergy, where the analgesic activity Diclofenac is effective in treating lateral epicondylitis exceeds that from a simple additive effect of the agents (Burnham et al. 1998). (Kolesnikov et al. 2000). Moore et al. (1998) showed that topical NSAIDs were significantly more effective than placebo in the treat- Side Effects ment of acute sprains and strains, with an  NNT Application of topical local anaesthetics does not result (number needed to treat) of 3.9; and chronic arthritis in clinically significant plasma levels causing side ef- and rheumatism, for which the NNT was 3.1. Keto- fects (Galer 2001; Towlerton and Rice 2003). profen, felbinac, ibuprofen and piroxicam had similar, Topical Capsaicin T significant efficacy. As the natural history of soft tissue complaints tends to Mechanisms of Action beself-limiting,treatmentwithtopicalNSAIDsdoesnot Capsaicinisanextractofchilipeppers.Itisformulatedas necessarily alter the overall outcome. a topical application, which when applied to skin causes Topical NSAIDs are less effective for arthropathies, but anintenselypainfulburningsensation,byselectivelyde- have been shown to be effective in treating mild to mod- polarising small diameter sensory afferent neurons. Re- erate osteoarthritis (Hosie and Bird 1994). However, ev- peated application causes a desensitising or neurotoxic idence supporting their efficacy in osteoarthritis of the effect on nociceptors, which results in a prolonged “se- knee is not consistent (Vaile et al. 1998). lective local analgesia” (Sawynok 2003; Towlerton and Rice 2003). Desensitisation of skin results in an analge- siaeffect.CapsaicinstimulatesthereleaseofsubstanceP Side Effects and calcitonin gene-related peptide from peripheral and Cutaneous adverse reactions like erythema, burn- central terminals of sensory neurons. Their release is in- ing sensation, irritation and contact dermatitis occur hibited by the desensitisation effect (Sawynok 2003). in 1 to 2% of patients (Vaile et al. 1998). Asthma, renal and gastrointestinal side-effects have been reported. Applications and Efficacy However, as plasma concentrations of topical NSAIDs Evidence supporting the use of capsaicin in posther- are low compared to oral NSAIDs, gastrointestinal petic neuralgia and painful  diabetic neuropathy is side-effects are less severe and less frequent. There- unconvincing (Galer 2001; Towlerton and Rice 2003). fore, topical NSAIDs are promoted as a safer and more Evidence supports its use in osteoarthritis at a variety of cost-effective alternative. sites, including the hand and knee, and in rheumatoid 2490 Topiramate arthritis(Galer2001;TowlertonandRice2003).Itisuse- ful in non-specific neck pain (Mathias et al. 1995), clus- Topography ter headaches and post-mastectomy pain (Galer 2001). Anecdotal evidence attests to its  effectiveness in a  Magnetoencephalography in Assessment of Pain in range of other neuropathic pain conditions and facial Humans pain (Galer 2001). Capsaicin is often not sufficient as monotherapy for treating chronic pain. It appears to be useful only in conjunction with other therapies. Total Pain

Side Effects Definition Initial application of capsaicin, especially in the first Expression of suffering, particularly the expression of week, causes burning pain at the site of application psychological distress as pain. in 40–80% of patients (Towlerton and Rice 2003). This,  Cancer Pain Management, Interface between Cancer along with a therapeutic effect time-delay of at least a Pain Management and Palliative Care week, reduces patient compliance and continuation of use. References Touch Evoked Pain 1. Burnham R, Gregg R, Healy P, Steadward R (1998) The Effec- tiveness of Topical Diclofenac for Lateral Epicondylitis. Clin Journal Sports Med 8:78–81  Allodynia (Clinical, Experimental) 2. Galer B (2001) Topical Medications. In: Loeser JD (ed) Bonica’s Management of Pain, 3rd edn. Lippincott Williams & Wilkins, Philadelphia, pp 1736–1742 3. Hosie G, Bird H (1994) The Topical NSAID Felbinac versus Oral NSAIDs: A Critical Review. Eur J Rheumatol Inflam 14:21–28 Tourniquet Ischemia 4. Kolesnikov Y, Chereshnev I, Pasternak G (2000) Analgesic Syn- ergy between Topical Lidocaine and Topical Opioids. J Pharma-  col Exp Ther 295:546–551 Tourniquet Test 5. Mathias B, Dillingham T, Zeigler D, Chang A, Belandres P (1995) Topical Capsaicin for Chronic Neck Pain. Am J Phys Med Re- hab 74:39–44 6. Moore R, Tramer M, Carroll D, Wiffen P, McQuay H (1998) Quantitative Systematic Review of Topically Applied Tourniquet Pain Ratio Non–Steroidal Anti–Inflammatory Drugs. BMJ 316:333–338 7. Sawynok J (2003) Topical and Peripherally Acting Analgesics. Definition Pharmacological Reviews 55:1–20 8. Towlerton G, Rice A (2003) Topical Analgesics for Chronic Pain. It is calculated as follows: Ongoing Clinical Pain Match In: Jensen T, Wilson P, Rice A (eds) Clinical Pain Management Time/Tolerance Time X 100 where the Ongoing Clini- Chronic Pain. Arnold, London, 213–226 9. Vaile J, Davis P (1998) Topical NSAIDs for Musculoskeletal cal Pain Match time is the time point, since the begin- Conditions. Adis International Limited 56:783–799 ning of the Tourniquet Test, at which the patient reports a pain intensity that matches the clinical pain intensity; the Tolerance Time is the time the patient can tolerate Topiramate the ischemia in the Tourniquet Test.  Tourniquet Test Definition Anticonvulsant medication.  Migraine, Preventive Therapy Tourniquet Test

GIANCARLO CARLI Department of Physiology, University of Siena, Siena, Topographical Italy [email protected] Definition Synonyms Topographical refers to the arrangement or reference to regions of the body or of a body part, especially the re- Ischemic Test; Submaximum Effort Tourniquet Tech- gions of a definite and limited area of the surface. nique; Forearm Ischemia Procedure; Acute Ischemia  Postsynaptic Dorsal Column Projection, Anatomical Test; Forearm Occlusion Pain; Ischemic pain; Tourni- Organization quet Ischemia Tourniquet Test 2491

Definition ercise time lasts 80 sec. The schedule is presented to Ischemic  painiselicitedbyhavingthesubjectsqueeze the subject by means of tape-recorded signals a handspring exercises 20 times after a tourniquet is 4. aftercompletingthesqueezes,toremaininareclining inflated around his upper arm. The quality of sensa- positionandresthisarmathissidewiththetourniquet tion is dull-aching or stinging  muscular pain,which still inflated, not to move his arm until the pressure closely resembles most types of  pathologic pain,but has been released (see Fig. 1c) increases progressively after cessation of squeezing. 5. to rate, when asked at irregularly spaced intervals, the Test performance is measured in terms of elapsed time incoming sensations of pain according to a predeter- between cessation of squeezing and report of slight mined scale, which includes the following categories (threshold) and unbearable (tolerance) pain. Muscular of experience: 0 = none; 1 = slight; 2 = moderately pain from ischemic contractions, which is due to tran- distressing; 3 = very distressing; 4 = unbearable. Ir- sient stimulation of peripheral  nociceptors (LaMotte regular intervals should be used to minimize the cues and Campbell 1978), is based on the  algogenic ac- to the subject regarding the time he had tolerated the tions of protons (Issberner et al. 1996). Noxious forearm pain. ischemia also evokes substantial elevations in arterial  Pain threshold (slight pain) occurs after about blood pressure (Maixner et al. 1990) and activation 3–6 min, while unbearable pain (tolerance) varies of endogenous opioid systems (Goldstein and Grevert from 7 to 53 min (Smith et al. 1966; Smith et al. 1968). 1978), thus representing a  diffuse noxious inhibitory The latency of unbearable pain is usually called  pain controls (DNIC) paradigm (Willer et al.1989). tolerance, but formally it represents ischemia tolerance, A pneumatic tourniquet cuff connected to a computer i.e. the measurement of time elapsed since exercise controlled air compressor has been used recently to pro- termination (beginning of ischemia) and not since pain duce pressure pain (Polianskis et al. 2001). Computer- onset. When the cuff is released, pain intensity and ized cuff algometry may continuously control stimulus numbness sensations sharply decrease, but their time or adjust the pressure to maintain the programmed pain course, as not included in the formal test, have not been level. This set up, which elicits an increasing pain im- systematically investigated. mediately after tourniquet cuff application around the Several authors have modified the test, but the main gastrocnemius-soleus muscle, represents a highly con- changes that have improved the test have been pro- figurable tool for assessment of pain sensitivity by pres- posed by Moore et al. (1979). According to new sug- sure, but does not involve the ischemic mechanisms as gestions, the individual maximal grip strength of the does the classical tourniquet test described in this chap- non-dominant arm has to be assessed using an isometric ter. exerciser equipped with a force gauge (Fig. 1b). After lowering the arm, the squeeze exercise must start im- mediately after the cuff has been inflated to 200 mm Hg, Characteristics instead of 250, avoiding a pause of 60 sec. as suggested The need for a dependable experimental method to test by Smith et al. (1966). The individual grip strength newanalgesicsinmanwasoneofthemainmotivationsto should be kept at the fixed percentage (50 %) of the T modify the earlier techniques of producing  Ischemic maximum grip strength, in order to avoid fatigue and to Pain/Test (Lewis et al. 1931, Hewer and Keele 1948), reduce inter-subject differences. The measurement of by changing from maximum to submaximum squeezing elapsed time should begin at the time of blood pressure effort. cuff inflation, i.e. at the beginning of the ischemia, rather Originally, the  submaximum tourniquet test (Smith et than at exercise termination. In addition, the rating must al. 1966; Smith et al. 1968) was suggested with the fol- be in a visual analog scale from 0 (no pain) to 100 (pain lowing order (see Fig. 1a, b, c). so severe that you would commit suicide if you had to The subject, reclining on a bed, is asked to comply with bear it for more than a few minutes). the following procedure: In the same research (Moore etal. 1979), itwasobserved that the amount of exercise used during the submaximal 1. to extend his non-dominant arm toward the ceiling effort tourniquet test significantly affected the level of and, with the arm raised, an Esmarch bandage is reported pain intensity versus time elapsed: in fact, by wrapped from the fingers to the elbow to drain the increasing the duration of each contraction from 0.6 sec. arm of venous blood (see Fig. 1a) to 2 sec, the threshold pain intensity was reached much 2. to apply a tourniquet bandage around the upper arm more rapidly. and inflate it to obtain a pressure of 250 mm Hg, to abolish arterial supply and to render the arm hypoxic 3. to lower the arm, remove the band and, after a pause Tourniquet Pain Ratio: A Method to Evaluate Clinical Pain of 60 sec, to squeeze a hand spring exerciser 20 times Sternback et al. (1974) originally suggested that the ex- while his arm is rested. Each squeeze is timed to last perimental pain generated by ischemic exercise could 2 sec followed by a 2 sec rest, so that the whole ex- be used to evaluate the severity of the ongoing clinical 2492 Tourniquet Test

Tourniquet Test, Figure 1 Main phases of the tourniquet test. (a) elevation of the bandaged forearm; (b) squeezes of isometric exerciser while the pneumatic tourniquet remains inflated to block forearm circulation; (c) arm at rest while the tourniquet is still inflated. pain. This method, called  Tourniquet Pain Ratio,re- in electrical threshold to evoke muscle pain (Pantaleo et quiresthepatientstoreportwhentheirarmpainintensity al. 1988), cutaneous warming pain threshold (Pertovara matchesthe clinical pain intensity: thistime point isthen et al. 1982) and in other sensory modalities. In patients used to measure the subjective severity of patient’s clin- with ongoing pain, it has been established that pain by ical pain and is calculated as follows: (Ongoing Clinical clinical origin does not stimulate DNIC on ischemic Pain Match Time / Tolerance Time) X 100. This method or thermal pain perception (Ekbloom and Hansson has several limitations, mainly because the Tourniquet 1987; Hansson et al.1988). On the contrary, forearm Pain Matching Score is significantly lower than the pa- ischemia elicited by the procedure of the submaximum tient’s own pain estimate (Moore et al. 1979). As for the tourniquet test elicits a generalized non-segmental in- relationshipbetweenpainintensityandelapsedtime,the hibition of tooth pain, resulting from acute irreversible dataindicatethatthepainratingsproducedbythetestare pulpitis (Sigurdsson and Maixner 1994). The latter not a linear function of elapsed time but rather a sigmoid effects remain for at least 5 minutes after removal of shaped curve. Nonetheless, the Touriquet Pain Ratio is the tourniquet, while the arm is free from pain. It has still used to provide an additional index of clinical pain to be underlined that the mechanisms of DNIC are not modulation (Sigurdsson and Maixner 1994). univocal since, for instance, the tourniquet test elicits inhibition of static mechano-allodynia sensations, trig- Tourniquet Test in the Diagnosis of Altered Nociceptive Trans- gered by pressure stimuli, but has no effect on dynamic mission mechano-allodynia sensations, elicited by brushing Both threshold and tolerance to ischemic pain has been (Bouhassira et al. 2003). In fibromyalgia and painful repetitively tested in clinical syndromes such as local- osteoarthritispatientstheprocedureofthesubmaximum ized musculoscheletal pain,  fibromyalgia, peripheral tourniquet test does not elicit modulation of pressure neuralgias, bulimia, hypertension and other conditions pain, as opposed to controls (Kosek et al. 1966), while in which a dysfunction in the excitability of the nocicep- the DNIC is still effective in patients suffering from tive system is expected. long-term trapezius myalgia.

Tourniquet Test and DNIC Touniquet Test and Drug Screening The efficacy of DNIC, the neurophysiological mecha- It has been repeatedly established that placebo and sug- nism that underlines the long established clinical phe- gestions of analgesia, both in subjects who are awake nomenon of  counterirritation (Wand-Tetley 1956), and during hypnosis, can reduce pain elicited by the has been successfully tested in healthy subjects follow- tourniquet test. Similarly, small doses of opiates (mor- ing the procedure of the submaximum tourniquet test, phine, dipipanone, codeine) and the NMDA-receptor Toxic Neuropathies 2493 antagonist ketamine display analgesic effects. On the 15. Polianskis R, Graven Nielsen T, Arendt-Nielsen (2002) Spatial contrary, the NMDA-receptor antagonist dextromethor- and Temporal Aspects of Deep Tissue Pain Assessed by Cuff Algometry. Pain 100:19–26 phan, diazepan and anti-inflammatory drugs such as 16. Sigurdsson A, Maixner W (1994) Effects of Experimental and aspirin or indomethacin do not affect ischemic pain. Clinical Noxious Counterirritants on Pain Perception. Pain Finally, adenosine, which mediates ischemic pain in 57:265–275 humans, at low doses exerts analgesic effects on the 17. Smith GM, Egbert LD, Markowitz RA et al. (1966) An Exper- imental Pain Method Sensitive to Morphine in Man: The Sub- tourniquet pain by membrane-bound peripheral adeno- maximum Effort Tourniquet Technique. J Pharmacol Exp Ther sine receptors (Eriksson et al. 2000). 154:324–332 18. Smith GM, Lowenstein E, Hubbard JH et al. (1968) Experi- Concluding Remarks mental Pain Produced by the Submaximum Effort Tourniquet Technique: Further Evidence and Validity. J Pharmacol Exp Ther In conclusion, the tourniquet test can provide useful 163:468–474 indications about individual reactivity and tolerance 19. Sternbach RA, Deems LM, Timmermans G et al. (1977) On the to deep ischemic stimuli, both in healthy subjects and Sensitivity of the Tourniquet Pain Test. Pain 3:105–110 in patients. There are, however, some limitations to be 20. Wand-Tetley JI (1956) Historical Methods of Counter-Irritation. Ann Phys Med 3:90–98 underlined. First of all, in patients suffering from deep 21. Willer JC, DeBroucker T, LeBars D (1989) Encoding of Noci- pressure pain or other deep pains in the forearms, un- ceptive Thermal Stimuli by Diffuse Noxious Inhibitory Controls bearable pain can occur following the application and/or in Humans. J Neurophysiol 62:1028–1038 inflation of the bandage. Moreover, the tourniquet pro- 22. Williams MW (1959) Ischemic Arm Pain and Non-Narcotic Analgesics. Toxicol Appl Pharmacol 1:590–597 cedure has shown a considerable between subjects and between session variability (Sigurdsson and Maixner 1994), and the sensitivity displayed may be inadequate to assess the analgesic effects of some pharmacological Toxic Neuropathies agents (Sternbach et al. 1977). SUNG-TSANG HSIEH Department of Anatomy and Cell Biology and References Department of Neurology, National Taiwan University, 1. Bouhassira D, Danziger N, Atta N et al. (2003) Comparison of the Taipei, Taiwan Pain Suppressive Effects of Clinical and Experimental Painful [email protected] Conditioning Stimuli. Brain 126:1068–1078 2. ErikssonBE, SadigB, SvedenhagJ et al. (2000) Analgesic Effects of Adenosine in Syndrome X are Counteracted by Theophylline: Definition A Double-Blind Placebo-Controlled Study. Clin Sci 98:15–20 3. Ekblom A, Hansson P (1987) Thermal Sensitivity is not Changed Toxic neuropathies are peripheral nerve disorders dueto by Acute Pain or Afferent Stimulation. J Neurol Neurosurg Psy- acute or chronic adverse effects of chemicals or medi- chiat 50:1216–1220 cations which occur in individuals or as an outbreak in 4. Goldstein A, Grevert P (1978) Placebo Analgesia, Endorphins a certain population after occupational exposure or en- and Naloxone. Lancet 2:1385 5. Hansson P, Ekbloom A, Lindblom U et al. (1988) Does Acute vironmental contamination. Intraoral Pain Alter Cutaneous Sensibility? J Neurol Neurosurg Psychiat 51:10032–1036 Characteristics T 6. Hewer AJ, Keele CA (1948) A Method of Testing Analgesics in Man. Lancet 2:683–688 Neurons, Axons and Neuropathy 7. Issberner U, Rehe PW, Steen KH (1996) Pain due to Tissue Aci-  Neuropathies are diseases of the peripheral nervous dosis: A Mechanism for Inflammatory and Ischemic Myalgia? system from variousetiologies, includingmetabolic dis- Neurosci Lett 208:191–194   8. Kosek E, Ekholm J, Hansson P (1966) Sensory Dysfunction in orders, such as diabetic neuropathy due to diabetes Fibromyalgia Patients with Implications for Pathogenic Mech- mellitus (Vinik AI et al. 2000), and toxic effects of anisms. Pain 68:375–383 chemotherapy for cancer. In the peripheral nervous 9. LaMotte RH, Campbell JN (1978) Comparison of Responses of  Warm and Nociceptive C-Fiber Afferents in Monkey with Human system, the length of axons is much greater than Judgements of Thermal Pain. J Neurophysiol 41:509–528 the diameter of the neuronal cell body. This results in 10. Lewis D, Pikering GW, Rothschild P (1931) Observations upon a much larger cytoplasmic volume in the entire axon Muscular Pain in Intermittent Claudication. Heart 15:359–383 compared to the volume of the neuronal cell body, often 11. Maixner W, Gracely RH, Zuniga JR et al. (1990) Cardiovascular and Sensory Responses to Forearm Ischemia and Dynamic Hand by several orders of magnitude. As an example, take Exercise. Am J Physiol 259:R1156–R1163 a motor neuron of an adult human. The diameter of a 12. Moore PA, Duncan GH, Scott DS et al. (1979) The Submaximal motor neuron in the lumbar spinal cord is up to 100 μm; Effort Tourniquet Test: Its use in Evaluating Experimental and in contrast, the length of a motor axon from this motor Chronic Pain. Pain 6:375–382 13. Pantaleo T, Duranti R, Bellini F (1988) Effects of Heterotopic neuron innervating the foot muscles is up to 1 m in Ischemic Pain on Muscular Pain Threshold and Blink Reflex in length. This greatly differs from other cells in the body, Humans. Neurosci Letter 85:56–60 such as fibroblasts, which have a cellular extension of 14. Pertovara A, Kemppainen P, Johannson G et al. (1982) Ischemic only a limited length. Pain Nonsegmentally Produces a Predominant Reduction of Pain and Thermal Sensitivity in Man: A Selective Role for Endoge- To maintain such unusual structural requirements, ax- nous Opioids. Brain Res 251:82–93 ons possess a rather complicated cytoskeletal system 2494 Toxic Neuropathies

(Griffin et al. 1995). Components of the  cytoskeleton type. An example of a primarily demyelinating neu- include microtubules (> 24 nm), intermediate filaments ropathy is tellurium-inducedtoxic neuropathy(Bouldin (10 nm), and microfilaments (6–8 nm) according to their et al. 1988). diameters and composition. These cytoskeletal proteins interact with each other through associated proteins, Clinical Applications such as microtubule-associated proteins, to form a Peripheral neuropathies are common neurological dis- three-dimensional interlacing structure. In addition, the orders of the community with an annual incidence metabolic demands of axons heavily depend on the neu- of 100–200 per 100,000 people. Toxic neuropathies ronal cell body, and an  axoplasmic transport system account for a minor proportion of etiology (–5%) has developed to transport materials both to and from depending on economical and medical factors and ge- neuronal cell bodies. Some cytoskeleton-associated ographic distribution. In the 1950-1970’s, most toxic proteins, such as the kinesin and dynein superfamily, neuropathies have been related to outbreaks of indus- are also responsible for transporting organelles and trial chemicals, such as acrylamide and organic solvents neurotransmitter containing vesicles (Hirokawa 1998). (hexacarbons). The list of these etiologies depends on Peripheral nerves, particularly those in nerve terminal the industrial development of different countries. Over regions, are distributed throughout the entire body, and the past decades, major outbreaks of toxic neuropathy are thus the most vulnerable part of the nervous system have decreased to a great extent due to stricter regulation during toxin exposure and metabolic derangement. of chemicals used in industry. Consequences of these insults, including dysregulated In recent years, most reported toxic neuropathies have cytoskeletal maintenance or blockade of  axonal been due to side effects of medications or from acciden- transport, may impair the functioning of axons, and tal exposure. Common chemotherapeutic agents caus- eventually result in  axonal degeneration. Alterna- ing toxic neuropathies include cis-platinum, taxol, and tively, neurons are vulnerable to toxins via systemic thalidomide. Thus, toxic neuropathies are relatively un- absorption. Toxins directly act on neuronal cell bodies, common compared to other etiologies, such as diabetes resulting in neuronal cell death and subsequent axonal mellitus, genetic neuropathies and inflammatory disor- degeneration. ders. Nevertheless, toxic neuropathieshave greatimpact on environmental and industrial regulation, and serve as Structural Organization of Peripheral Nerves and Pathology of importantmodelsforinvestigatingmechanismsofnerve Toxic Neuropathies injury and the correlation between pathology and clin- The structural organization of peripheral nerves in- ical manifestations. cludes two major cellular components: neurons with cytoplasmic extensions and axons, and ensheathing Clinical Manifestations of Toxic Neuropathies glia ( Schwann cells) with myelin sheaths, modified Functionally, the peripheral nervous system consists membranous insulating materials. Nerve injury in toxic of motor, sensory, and autonomic nerve fibers (Fig. 1). neuropathies occurs at different levels along the neural Motor nerves and proprioceptive nerves, which convey axis through different mechanisms. Toxins can act on sensory information from bones, muscles, and joints, neuronal components (neuronal cell bodies, axons, and are large  myelinated nerves (large-diameter nerves nerve terminals) and glial components (Schwann cells or  large fibers). Nociceptive, thermal, and autonomic and myelin sheaths). Neuronal degeneration results in nerves belong to small myelinated nerves or unmyeli- subsequent nerve fiber degeneration. Most frequently, nated nerves (small-diameter nerves or  small fibers). the major target site is at axons, either proximally or dis- All of these nerve fibers have different cytoskeletal tally along the nerve fibers, while neuronal cell bodies organizations, origins, and terminals (Chen et al. 1999). largely remain intact. The common outcome is axonal The severity of neurological deficits depends on several degeneration, or Wallerian-like degeneration, and sec- factors, including the vulnerability of each nerve fiber ondary demyelination. The pathology of most toxic type, the duration of toxin exposure, the total dose of neuropathies is axonal degeneration, particularly of the toxins, and the extent of nerve degeneration. A major distal axons, such as with  acrylamide (Schaumburg factor in determining clinical presentations is the differ- et al. 1974). Only rare experimental toxins, such as ential susceptibility of neurons to toxins or pathologic β,β’-iminodipropionitrile, act on proximal axons (Grif- processes, a characteristic of neurological diseases: for fin et al. 1983). If a toxin selectively damages Schwann example, motor neuronsin amyotrophic lateralsclerosis cells or impairs myelin organization, neuropathies of (Lou Gehrig’s disease), cortical neurons in Alzheimer’s primary demyelination will develop. Because of con- disease, and substantia nigra neurons in Parkinson’s duction failure in primary  demyelination,themajor disease. Each disease has a distinct pattern of clinical electrophysiological abnormality of  demyelinating presentation because certain parts of the nervous system neuropathy is the marked slowing of nerve conduction. are selectively damaged. Thistype of toxic neuropathyisrelatively rarecompared Clinical manifestations of neuropathies, therefore, de- to neuropathies of the primarily axonal degeneration pend on the damage to different fiber types (Thomas Toxic Neuropathies 2495

Toxic Neuropathies, Figure 1 Structural organization of peripheral nerves. Peripheral nerves consist of: (1) motor nerves from ventral horn motor neurons of the spinal cord (black), (2) proprioceptive nerves from large-diameter sensory neurons of dorsal root ganglia which terminate in skeletal muscles, tendons, and joints (olive), and (3) nociceptive and thermal nerves from small-diameter sensory neurons of dorsal root ganglia which terminate in the skin (pink) and autonomic nerves from autonomic ganglia innervating smooth muscles and glands (blue).

and Ochoa 1993). When motor nerve fibers are in- Classification of Toxic Neuropathies: jured, neurological deficits range from mild weakness Sources of distal limb muscles to marked paralysis of all four • Environmental contaminants: lead limbs. When sensory nerves responsible for joint move- • Occupational outbreaks: n-hexane ments are injured, unsteadiness during walking may T • Adverse effects of medications: cisplatin develop. This type of neuropathy is sometimes called • Accidental exposure or ingestion: lead  Large Fiber Neuropathy. On the other hand, in pa- • Experimentaluses:e.g.hexacarbons,2,5-hexanediol, tients with damaged sensory nerves, neuropathic pain, acrylamide, capsaicin such as tingling or electric-shock sensations can be experienced. Various autonomic complaints, such as Functional components tachycardia, constipation, or diarrhea can be presenting • Motor neuropathy: lead symptoms in patients with damaged autonomic nerves. • Sensory neuropathies Sensory neuropathy with painful features and loss of nociceptive functions and autonomic neuropathy are – Proprioceptivetype:cis-platinum,vincristine,iso- termed as  small-fiber neuropathy. Often, neurolog- niazid ical presentations are combined effects due to deficits – Nociceptive type: capsaicin of different fibers types: for example, a patient with motor, sensory, and autonomic neuropathy may have • Autonomic neuropathy: acrylamide, alcoholic, ar- manifestations of weakness, sensory disturbances, and senic (inorganic), diphtheritic toxin dysautonomia. Various etiologies of toxic neuropathies with their pathologic mechanisms and manifestations Clinical presentations are summarized below. This list is not intended to be • Weakness a comprehensive catalogue, and readers can refer to • Sensory disturbances: neuropathic pain, hypesthesia various sources for detailed information (Spencer and • Dysautonomia Schaumburg 2000). 2496 Toxic Neuropathies

Structural components strated in both humans and experimental animals over the past few decades: for example, neuropathies due • Large myelinated nerves to exposure to hexacarbons, particularly the active – Motor nerves: acrylamide components, 2,5–hexanediol, acrylamide, and carbon – Sensory nerves (proprioception): n-hexane disulfide. The longest and largest nerves are affected earlier, with the major pathology in the terminal parts of axons, i.e.  distal axonopathy. Intoxication results • Small myelinated nerves from absorption of organic solvents in poorly venti- – Sensory nerves (thermal sense, nociception): cap- lated environments. Fig. 2 illustrates the scenario of saicin pathology in neuromuscular junctions after hexacar- – Autonomic nerves: acrylamide, alcoholic, arsenic bon and acrylamide intoxication (Ko et al. 1999). In (inorganic), diphtheritic toxin animals intoxicated with such compounds as, for ex- ample, acrylamide, there is no visible weakness or ataxia during the early phase. At that stage, however, • Unmyelinated nerves motor nerve terminals have already begun to swell up. – Sensory nerves (thermal senses, nociception): Obvious weakness and ataxia of hind limbs gradually capsaicin develops. The weakness and unsteadiness progress at – Autonomic nerves: acrylamide, alcoholic, arsenic variable speeds, and eventually the forelimbs are af- (inorganic), diphtheritic toxin fected, resulting in quadriparesis at the late stage. As intoxication proceeds, axonal swelling extends from Sites of actions and mechanisms junctional folds into the intramuscular nerves, which results in Wallerian-like degeneration of motor nerves • Proximal axons: filamentous swelling and denervation of neuromuscular junctions (Fig. 2a). – β,β’-iminodipropionitrile Similar changes also develop in the central terminals of long axons, such as terminals of the posterior column at the brainstem, the central axons of dorsal root ganglia, • Terminal portion: swelling and degeneration thus the term,  central-peripheral distal axonopathy, – Neuromuscular junctions: 2,5-hexanediol, acry- or  dying-back neuropathy (LoPachin 2000). lamide – Pacinian corpuscles: 2,5-hexanediol Nociceptive Nerves in Toxic Neuropathies – Epidermalnervesoftheskin:acrylamide,cisplatin Nociceptive nerves subserving thermal sensations are Aδ or C fibers based on physiological classification, Pathology with diameters in the range of 1–5 μm. These axons, with  free nerve endings, are peripheral processes of • Primarily axonal degeneration: hexacarbon small neurons in  dorsal root ganglia, and terminate • Primarily demyelination: tellurium in the most-superficial layer of the skin, the epidermis The terminals of the longest nerves are the most sus- (Fig. 1). Their central processes end in the dorsal horn ceptible part during toxin exposure, and clinical symp- and synapse with spinothalamic and other nociceptive toms usually develop in the corresponding innervated neurons. Due to their small size, these nerve fibers areas of these damaged nerves in the early phase of toxic have traditionally been studied with high-resolution neuropathy. In addition, clinical symptomsandsignsare  electron microscopy. The application of sensitive usually more severe in regions with early-onset symp-  immunohistochemistry with various neuronal mark- toms than in regions with late-onset symptoms. For ex- ers has enabled the evaluation of skin innervation at ample, numbness and neuropathic pain may appear in a global scale (Hsieh et al. 2000). Among these neu- the toes and feet earlier than in the legs and thighs. Sim- ronal proteins, protein gene product 9.5, an ubiquitin ilarly, symptoms in the fingers and hands are earlier than C-terminal hydrolase, is particularly useful for demon- those in the forearms. Neurological deficits are usually strating the rich innervation of the epidermis (Fig. 2b). more severe in the lower limbs than in the upper limbs. Based on technical improvements, it is now possible This “glove-stocking” type of distribution is character- to address the issue of neuropathy of small-diameter istic of length-dependent neuropathies, particularly for nerves due to toxin exposure. the majority of toxic neuropathies, although exceptions  Capsaicin is an active compound from hot peppers, may exist in certain types of toxic neuropathies. which is known to activate the vallinoid receptor. A ma- jor use of capsaicin ointment is to treat neuropathic pain; Therapeutic Consequences its efficacy probably occurs through damage to sensory Evolution of Pathology in Toxic Neuropathies nerve endings. Systemic injection of capsaicin in neona- The typical pathology of toxic neuropathies of large- tal rats abolishes primary afferent terminals in the dorsal diameter motor and sensory nerves has been demon- horn of the spinal cord (Wall et al. 1982). In human stud- Toxic Neuropathies 2497

Toxic Neuropathies, Figure 2 Diagram of the progression of toxic neuropathy. The diagram illustrates degeneration of nerve terminals in neuromuscular junctions (a) and in the epidermis of the skin (b) during the evolution of toxic neuropathy with acrylamide-induced neuropathy as an example. Axons and nerve terminals were immunostained with protein gene product 9.5 (dark brown), and neuromuscular junctions with substrates of cholinesterase (blue). (a) In normal muscles, motor nerve terminals travel into every fold of the neuromuscular junction (NMJ) with quite-uniform thickness. In the early phase of degeneration, focal swelling of nerve terminals in the neuromuscular junctions develops, and axonal swelling extends into the motor nerve trunks. Finally in the late stage, neuromuscular junctions are denervated, and motor nerves become degenerated with a segmented appearance. (b) Bundles of nerve fibers form subepidermal nerve plexuses (SNP) in the dermis (DERM) below the epidermis (EPI) in normal skin. Epidermal nerves arise from the subepidermal nerve plexuses, and ascend vertically in the epidermis with a varicose appearance. In the early phase of degeneration, epidermal nerves become swollen, and branching increases. During the late phase, epidermal nerves disappear, and the epidermis becomes denervated. Subepidermal nerve plexuses have a fragmented appearance, indicating that they are undergoing degeneration. ies, capsaicin causes degeneration of nerve terminals in onal structures and changes in synaptic plasticity. For the epidermis after local application, with correspond- example, different subtypes of sodium channels are ing loss of thermal sensations in the application area (Si- up-regulated or down-regulated in animals with neu- mone et al. 1998). A certain degree of epidermal nerve ropathic pain. In damaged nerves, sodium channels regeneration can later be observed, suggesting that the are re-distributed along the entire axons or accumulate major target of capsaicin-induced nerve damage by lo- in the neuroma, instead of clustering around the node cal treatment is at the terminal portion, instead of at the of Ranvier in normal axons. Many of these changes neuronal cell body. may contribute to the generation and maintenance of Traditionally, acrylamide and cisplatin have been con- neuropathic pain. sidered to cause neuropathy of large-diameter nerves. Our knowledge of toxic neuropathies has broadly The development of staining for cutaneous nerve ter- expanded over the past decade because many new minals allowed the influence of acrylamide on small- investigative techniques have been developed, particu- diameter sensory nerves in the skin to be assessed (Fig. larly toxic neuropathies of nociceptive nerves, whose T 2b). At the initial stage of intoxication,  epidermal dysfunctions cause diverse manifestations of neuro- nerves show two major changes: terminal swelling and pathic pain. The identification of environmental toxins increased branching (Ko et al. 2002). There is a progres- as etiologies of neuropathies provides new insights into sive reduction in epidermal nerve density thereafter. At mechanisms of nerve degeneration and its consequent the late stage, there is significant dermal nerve degen- neuropathicpain. Agoodexampleis2,5-hexanediol,the eration with ultrastructural demonstration of vacuolar active metabolic product of organic solvents containing changes. These findings have established the patho- hexacarbons. The recognition of hexacarbon-induced logical consequences of acrylamide neurotoxicity in central-peripheral distal axonopathy has provided a cutaneous sensory nerves for studying the“dying-back” new model and opened a new field to understand nerve pathology of nociceptive nerves. These phenomena are degeneration. The causes of a considerable proportion quite similar to the pathology of cutaneous nerves (10–20%) of peripheral neuropathies have not yet been in human skin, including epidermal nerve swelling, identified. Among these neuropathies, toxin-exposure increased branching points of epidermal nerves, and has rarely been explored. Detailed investigation of ex- fragmentation of dermal nerve fibers. posure history is mandatory, and may offer a new look Neuropathic pain is an important manifestation of some at some neuropathies of unknown etiology. toxicneuropathies,suchascis-platinumandvincristine- References induced neuropathies. The exact mechanisms remain obscure. Responses to nerve injury include neuronal 1. Bouldin TW, Samsa G, Earnhardt TS, Krigman MR (1988) Schwann Cell Vulnerability to Demyelination is Associated and glial responses at the levels of transcription and with Internodal Length in Tellurium Neuropathy. J Neuropathol post-translation, re-organization of neuronal and ax- Exp Neurol 47:41-47 2498 Traction

2. Chen WP, Chang YC, Hsieh ST (1999) Trophic Interactions be- Characteristics tween Sensory Nerves and the Targets. J Biomed Sci 6:79-85 3. Griffin JW, Fahnestock KE, Price DL, Cork LC (1983) Cy- Mechanism toskeletal Disorganization Induced by Local Application of beta, beta’–iminodipropionitrile and 2,5–hexanedione. Ann No mechanism has been established whereby traction Neurol 14:55-61 might relieve pain. Nevertheless, proponentsof traction 4. Griffin JW, George EB, Hsieh ST, Glass JD (1995) Axonal De- believe that it works, and have speculated on its mech- generation and Disorders of the Axonal Cytoskeleton. In: Wax- man SG, Kocsis JD, Stys PK (eds) The Axon, Oxford University anism of effect (Krause et al. 2000). Press, New York, pp 375-390 There is clear evidence that spinal traction does sepa- 5. Hirokawa N (1998) Kinesin and Dynein Superfamily Proteins ratevertebralbodies.However,inthelumbarspinemuch and the Mechanism of Organelle Transport. Science 279:519-526 of the separation observed arises from flattening of the 6. Hsieh ST, Chiang HY,Lin WM (2000) Pathology of Nerve Termi- nal Degeneration in the Skin. J Neuropathol Exp Neurol 59:297- lumbar lordosis (Twomey 1985). In the cervical spine, 307 30 pounds of traction achieves only fractions of a mil- 7. Ko MH, Chen WP, Hsieh ST (2002) Neuropathology of Skin limetre separation between vertebral bodies, amounting Denervation in Acrylamide-Induced Neuropathy. Neurobiol Dis to 2 mm total elongation anteriorly and 6 mm posteri- 11:155-165 8. Ko MH, Chen WP, Lin-Shiau SY, Hsieh ST (1999) Age- orly between C2 and T1 (Colachis and Strohm 1969). Dependent Acrylamide Neurotoxicity in Mice: Morphology, The purported benefit of this separation is, however, am- Physiology, and Function. Exp Neurol 158:37-46 biguous. 9. LoPachin RM (2000) Redefining Toxic Distal Axonopathies. When traction is used to treat radicular pain, the im- Toxicol Lett 112-113:23-33 10. Schaumburg HH, Wisniewski HM, Spencer PS (1974) Ultra- plicitmechanismisdecompressionoftheaffectedspinal structural Studies of the Dying-Back Process. I. Peripheral Nerve nerve. However, separation of vertebrae increases the Terminal and Axon Degeneration in Systemic Acrylamide In- longitudinal dimension of the intervertebral foram- toxication. J Neuropathol Exp Neurol 33:260-284 11. Simone DA, Nolano M, Johnson T, Wendelschafer-Crabb G, ina but longitudinal compression of spinal nerves is Kennedy WR (1998) Intradermal Injection of Capsaicin in Hu- an uncommon phenomenon. Most commonly, spinal mans Produces Degeneration and Subsequent Reinnervation of nerves are affected in the sagittal dimension, anteriorly Epidermal Nerve Fibers: Correlation with Sensory Function. J by disc herniations or osteophytes or posteriorly by Neurosci 18:8947-8959 12. Spencer PS, Schaumburg HH (2000) Experimental and Clinical osteophytes of the zygapophysial joints. Longitudinal Neurotoxicology. Oxford University Press, New York separation does not relieve encroachment in the sagittal 13. Thomas PK, Ochoa J (1993) Clinical Features and Differential dimension. Moreover, upon the patient resuming the Diagnosis. In: Dyck PJ, Thomas PK, Griffin JW,Low PA,Poduslo upright posture, any benefit of traction is immediately JF (eds) Peripheral Neuropathy, W.B.Saunders, Philadelphia, pp 749-774 lost, as gravity restores the compression load on the 14. Vinik AI, Park TS, Stansberry KB, Pittenger GL (2000) Diabetic spine. Indeed, its has been shown that, without rising, Neuropathies. Diabetologia 43:957-973 after simply resting on the traction table for 20 min, the 15. Wall PD, Fitzgerald M, Nussbaumer JC, Van der Loos H, Devor effects of cervical traction are all but lost (Colachis and M (1982) Somatotopic Maps are Disorganized in Adult Rodents Treated Neonatally with Capsaicin. Nature 295:691-693 Strohm 1969). Another conjecture is that traction reduces disc her- niations. The available data, however, are limited and conflicting. In one small study, although traction did Traction reduce disc herniations in two of three patients, the SUSAN MERCER protrusions reappeared within 14 min after release of School of Biomedical Sciences, University of the force (Matthews 1968). Queensland, Brisbane, QLD, Australia In the absence of firm evidence for a mechanical effect [email protected] of traction, some authorities have pursued alternative rationales, such as silencing ectopic impulse genera- Synonyms tors and normalisation of conduction in spinal nerves (Krause et al. 2000). These speculations, however, nev- Intermittent; progressive adjustive; manual or continu- ertheless presuppose that traction reverses compression ous traction; autotraction; gravity-assisted traction; self of the spinal nerve by separating the vertebral bodies. traction; unloading They also require that relatively brief traction somehow achieves lasting reversal of the pathophysiology that Definition causes pain. Traction is a treatment for spinal pain. It involves ap- Thereisevenlessofaphysiologicalrationalefortraction plying a pulling force to the lower limbs or to the head, when it is applied for spinal pain, as opposed to radicu- in order to separate the vertebrae of the spine and / or lar pain. In the first instance, nerve root irritation causes to stretch the surrounding muscles and ligaments. pain in the limbs, not in the back or inthe neck. The ratio- The traction force may be delivered manually, or via nalefortractionforspinalpain,therefore,cannotinvolve weights, pulleys or mechanical devices as a continuous, decompression of spinal nerves. Instead, it has been pro- sustained, intermittent or intermittent pulsed force. posed that perhaps spinal pain might be relieved by “in- Traditional Pharmacological Pain Relief 2499 creasing non-nociceptive input and recruitment of de- isatreatment,steepedintraditionbutdevoidofevidence. scendinginhibition”(Krauseetal.2000).Whileperhaps  Lumbar traction attractive as a conjecture, such a statement falls short of actually constituting evidence of how traction might References relieve spinal pain. Another proposition is that traction 1. Aker PD, Gross AR, Goldsmith CH et al. (1996) Conservative servesto stretch spinaltissues(Krause etal. 2000),butin management of mechanical neck pain: systematic overview and that event it is questionable whether elaborate and pas- meta-analysis. BMJ 313:1291–1296 2. Beurskens AJ, de Vet HC, Koke AJ et al. (1997) Efficacy of sive traction offers any advantage over simple stretch- traction for non-specific low back pain: 12-week and 6-month ing exercises that the patients can undertake themselves. results of a randomized clinical trial. Spine 22:2756–2762 The proposition that traction reduces intervertebraldisc 3. Bogduk N, McGuirk B (2006) Medical Management of Acute pressures is confounded not only by the lack of experi- and Chronic Neck Pain. An Evidence-Based Approach. Elsevier, Amsterdam (in press) mental data that demonstrate this effect, but also by the 4. British Association of Physical Medicine (1966) Pain in the neck lack of a cogent theory as to how raised disc pressure and arm: a multicentre trial of the effects of physiotherapy. BMJ causes back pain and why that pain should stay relieved 1:253–258 5. Colachis SC, Strohm BR (1969) Effects of intermittent trac- once the traction is released and the patient resumes an tion on separation of lumbar vertebrae. Arch Phys Med Rehabil upright posture. 44:251–258 6. Coxhead CE, Inskip H, Meade TW et al. (1981) Multicentre trial Applications of physiotherapy in the management of sciatic symptoms. Lancet 1:1065–1068 Traction has been used to treat neck pain, cervical radic- 7. Goldie I, Landquist A (1970) Evaluation of the effects of different ular pain and radiculopathy, back pain and lumbar radic- forms of physiotherapy in cervical pain. Scand J Rehab Med 2–3:117–121 ular pain and radiculopathy. Some practitioners use it to 8. Harms-Ringdahl K, Nachemson A (2000) Acute and subacute treat thoracic spinal pain, but there is no literature on its neck pain: nonsurgical treatment. In: Nachemson A, Jonsson E efficacy for this condition. (eds) Neck and Back Pain: The Scientific Evidence of Causes, Traction can be applied manually by the therapist (man- Diagnosis, and Treatment. Lippincott Williams & Wilkins, Philadelphia, pp 327–338 ualtraction),byamotorizedpulley(motorisedlumbaror 9. Harte AA, Baxter GD, Gracey JH (2203) The efficacy of traction cervical traction), by the patients themselves providing for back pain: a systematic review of randomized controlled trials. the pulling force (autotraction) or by suspension from a Arch Phys Med Rehabil 84:1542–1553 device (gravitational traction) (Twomey 1985). 10. Klaber Moffett JA, Hughes GI, Griffiths P (1990) An investiga- tion of the effects of cervical traction. Part 1: clinical effective- ness. Clin Rehab 4:205-211 Efficacy 11. Krause M, Refshauge KM, Dessen M et al. (2000) Lumbar spine traction: evaluation of effects and recommended application for Systematicreviewshavebeen confoundedbytheirregu- treatment. Manual Therapy 5:72–81 larandinconsistentdiagnosticcriteriausedinthestudies 12. Matthews JA (1968).Dynamic discography: a study of lumbar reviewed. It has not always been evident if the patients traction. Ann Phys Med 9:275–279 hadsomaticpain,somaticreferredpainorradicularpain. 13. Matthews JA, Hickling J (1975) Lumbar traction: a double-blind controlled study for sciatica. Rheumatol Rehabil 14:222–225 Although some earlier reviews offered open or encour- 14. Pal B, Mangion P, Hossain MA et al. (1986) A controlled trial aging conclusions, these have been supplanted by sub- of continuous lumbar traction in the treatment of back pain and T sequent studies and reviews. sciatica. Brit J Rheumatol 25:181–183 No randomized controlled trials have shown if traction 15. Twomey LT (1985) Sustained lumbar traction. An experimental study of long spine segments. Spine 10:146–149 is effective for neck pain (Aker et al. 1996; Harms- Ringdahl and Nachemson 2000). The available studies indicated that it is not effective for acute neck pain (Bogduk and McGuirk 2006). For chronic neck pain, Tractus Trigeminothalamicus traction has not been subjected to scientific studies. For cervical radicular pain, studies have shown that traction  is no more effective than sham traction or placebo treat- Trigeminothalamic Tract Projections ment (British Association of Physical Medicine 1966; Goldie and Landquist 1970; Klaber et al. 1990). The same conclusions apply for the treatment of lumbar radicular pain (Coxhead et al. 1981; Matthews and Traditional Pharmacological Pain Relief Hickling 1975; Pal et al. 1986). For non-specific low back pain, traction is no more effective than a placebo Definition treatment (Beursken et al. 1997). Pain relieved by oral and subcutaneous injections of analgesic drugs when the patient demands pain relief. Indications Often ineffective in that doses are too low and dosing In the face of the available scientific evidence, there are intervals are too long. nolegitimateindicationsfortractioninthemodernera.It  Postoperative Pain, Acute Pain Team 2500 Trafficking

Multiple targeting domains have been discovered that Trafficking direct K+ channels to different sites within the neuron. The differential targeting of Kv2.1 and Kv2.2 to alter- Definition native dendritic regions is governed, at least in part, Trafficking refers to synthesis and targeting of proteins by a 26 amino acid  motif on the cytoplasmic tail of to specific locations within the cell. Kv2.1. Manganas et al. (2001) have found that specific  Opioid Receptor Trafficking in Pain States residues within the pore region of Kv1.× control sur-  Trafficking and Localization of Ion Channels face expression of those channels. Voltage-dependent ion channels are typically heteromultimers consist- ing of a pore-forming alpha subunit and one or more beta subunits that modulate gating. Kv channel beta Trafficking and Localization of Ion subunits are bound at the cytoplasmic surface of the Channels channel. It was recently found that beta subunits also 1 2 participate in localization. Axonal targeting of Kv1.2 in PETER SHRAGER ,MATTHEW N. RASBAND 1 hippocampal neurons is driven by the tetramerization Deptartment of Neurobiology and Anatomy, domain on the N-terminus, at a site that binds Kvbeta2 University of Rochester Medical Center, Rochester, (Gu et al. 2003). Kvbeta subunits have a binding pocket NY, USA 2 for NADP+, and mutation of this site eliminates their University of Connecticut Health Center, Farmington, axonal targeting capability (Campomanes et al. 2002). CT, USA Nodal regions have 3 major zones: the nodal gap; para- [email protected], [email protected] nodes in which axoglial junctions link the paranodal Synonyms loops to the axolemma; and the juxtaparanodes, zones that flank the paranodes, begin the internode, and have Voltage-Dependent Pores; Clustering; Targeting; Ion no special morphological characteristics. At nodal re- Channel Trafficking gions KCNQ2 and KCNQ3, slowly activating channels that can be modulated by neurotransmitters, are found Definition within the nodal gap (Devaux et al. 2004). Kv1.1 and  Ion channels are pore-forming proteins in the surface Kv1.2 are clustered in the juxtaparanodes in both the membrane through which electrical charges move PNS and CNS. The localization of Kv1.× is dependent to establish and alter the membrane potential. These on the integrity of the axoglial paranodal junctions. channels must be synthesized and inserted into the When the latter are disrupted, these K+ channels are membrane in the proper locations within the neuron found in the paranodes and diffusely throughout the in order for signaling to occur normally. internode. At both axon initial segments and  nodes of Ranvier, Characteristics voltage-dependent  Na +  channels are linked to Neurons are highly polarized cells, and during devel- the spectrin-actin cytoskeleton by the adapter protein opment individual neurites become either dendrites ankyrinG. AnkyrinG also serves to link Na+ chan- or axons. An essential element in this polarization is nels in a large molecular complex that includes the the proper  trafficking of proteins to these processes, L1–family proteins NrCAM and neurofascin. The and, in particular, the targeting of ion channels to spe- beta subunits of Na+ channels are membrane proteins cific locations. In dendrites, ligand-gatedchannels must and they, along with NrCAM, neurofascin, and con- accumulate at postsynaptic regions. In axons, Na+ chan- tactin (a GPI-anchored protein) are all members of nels are clustered at the initial segment, which is the the immunoglobulin superfamily, implicating them in site of integration of postsynaptic potentials and of ini- intercellular (perhaps neuron-glial) signaling. The link tiation of the action potential. Na+ and  K+ channels to ankyrinG also appears to be important in targeting. are distributed at low density throughout the remainder In spinal motor neurons in culture, Na+ channels are of the fiber and, if the axon is myelinated, they are normally synthesized in the soma, but are inserted in also clustered within specific zones in the region of the the surface membrane only at the axon initial segment node of Ranvier. Ectopic localization of these channels (Alessandri-Haber et al. 1999). Nav1.2 has a C-terminal can lead to repetitive or spontaneous firing, and can motif that is involved in axonal targeting. It has also thus contribute to pain. Localization may be controlled recently been demonstrated that the intracellular linker by domains within the protein that direct transport or betweendomainsIIandIIIservesasalocalizationsignal insertion to specific sites, or by differential rates of to the initial segment (Garrido et al. 2003). Of particular endocytosis. For example, a protein may be axonal interest, Lemaillet et al. (2003) showed that this latter because its endocytotic removal rate is much higher in loop contains an ankyrinG binding motif. Thus, estab- dendrites. There has been much progress recently in lishment of these regions of high Na+ channel density uncovering these mechanisms. appears to involve targeting to the axon and insertion in Trafficking of Proteins 2501 the surface membrane, followed by cytoskeletal immo- of these proteins may prove useful in the treatment of bilization via ankyrinG. In the case of nodes of Ranvier, these disorders. there is an additional requirement for glial modeling of the axonal surface. Myelinating Schwann cells in References + the PNS direct the clustering of Na channels, per- 1. Alessandri-Haber N, Paillart C, Arsac C, Gola M, Couraud F, haps by reorganizing the low density of these channels Crest M (1999) Specific Distribution of Sodium Channels in Ax- present throughout the axon prior to myelin formation ons of Rat Embryo Spinal Motoneurones. J Physiol 518:203–214 2. Boiko T, Rasband MN, Levinson SR, Caldwell JH, Mandel G, (Dugandzija-Novakovic et al. 1995). The neuron-glial Trimmer JS, Matthews G (2001) Compact Myelin Dictates the communication involved in this trafficking may involve Differential Targeting of Two Sodium Channel Isoforms in the the other members of the Na+ channel complex men- Same Axon. Neuron 30:91–104 tioned above (Custer et al. 2003). In the CNS, some 3. Campomanes CR, Carroll KI, Manganas LN, Hershberger ME, Gong B, Antonucci DE, Rhodes KJ, Trimmer JS (2002) Kv Beta early aspects of clustering may involve soluble factors Subunit Oxidoreductase Activity and Kv1 Potassium Channel released by oligodendrocytes, but final node formation Trafficking. J Biol Chem 277:8298–8305 seems to be contact dependent, as in the PNS (Kaplan et 4. Custer AW, Kazarinova-Noyes K, Sakurai T, Xu X, Simon al. 2001). Finally, there is a developmentally regulated W, Grumet M, Shrager P (2003) The Role of the Ankyrin- + Binding Protein NrCAM in Node of Ranvier Formation. J progression in Na channel subtype in axons. Nav1.2 is Neurosci 23:10032–10039 expressed early, and is later replaced by Nav1.6 (Boiko 5. Devaux JJ, Kleopa KA, Cooper EC, Scherer SS (2004) KCNQ2 et al. 2001). The physiological consequences of this is a Nodal K+ Channel. J Neurosci 24:1236–1244 shift are not known, but Nav1.6 has a unique resurgent 6. Devor M, Keller CH, Deerinck TJ, Levinson SR, Ellisman MH (1989) Na+ Channel Accumulation on Axolemma of Afferent current (Raman and Bean 1997), which could render Endings in Nerve End Neuromas in Apteronotus. Neurosci axons more susceptible to re-entry excitation that may Lett 102:149–154 contribute to pain, if other regulatory zones of nodes 7. Dugandzija-Novakovic S, Koszowski AG, Levinson SR, Shrager are compromised. For example, loss of juxtaparanodal P (1995) Clustering of Na Channels and Node of Ranvier For- mation in Remyelinating Axons. J Neurosci 15:492–502 Kv1.× can lead to instabilities. 8. Garrido JJ, Giraud P, Carlier E, Fernandes F, Moussif A, Fache Turnover rates of ion channels in myelinated axons MP, Debanne D, Dargent B (2003) A Targeting Motif Involved have not been measured directly, but some data are in Sodium Channel Clustering at the Axonal Initial Segment. + Science 300:2091–2094 available. Nodal Na channels are particularly stable, 9. Gu C, Jan YN, Jan LY (2003) A Conserved Domain in Axonal and clusters can be detected up to 9 days after myelin Targeting of Kv1 (Shaker) Voltage-Gated Potassium Channels. disruption (Custer et al. 2003). This is undoubtedly Science 301:646–649 due to the cytoskeletal link via ankyrinG. The stabi- 10. Kaplan MR, Cho MH, Ullian EM, Isom LL, Levinson SR, Bar- res BA (2001) Differential Control of Clustering of the Sodium lization of these channels seems to occur gradually Channels Na(v)1.2 and Na(v)1.6 at Developing CNS Nodes of after their initial clustering, and may involve the forma- Ranvier. Neuron 30:105–119 tion of large complexes through the multiple binding 11. Kretschmer T, England JD, Happel LT, Liu ZP, Thouron CL, sites of ankyrinG (Custer et al. 2003). Juxtaparanodal Nguyen DH, Beuerman RW, Kline DG (2002b) Ankyrin G and Voltage Gated Sodium Channels Co-Localize in Human Kv1.× channel clusters are significantly less stable, and Neuroma-Key Proteins of Membrane Remodeling after Axonal break up within 1–2 days after initiating demyelination Injury. Neurosci Lett 323:151–155 (Rasband et al. 1998). 12. Lemaillet G, Walker B, Lambert S (2003) Identification of a Con- T There is considerable evidence that altered ion channel served Ankyrin-Binding Motif in the Family of Sodium Channel Alpha Subunits. J Biol Chem 278:27333–27339 trafficking, localization, and turnover are involved in 13. Manganas LN, Wang Q, Scannevin RH, Antonucci DE, Rhodes painful neuropathies, although the precise mechanisms KJ, Trimmer JS (2001) Identification of a Trafficking Determi- remain to be determined. Painful neuromas develop nant Localized to the Kv1 Potassium Channel Pore. Proc Natl Acad Sci USA 98:14055–14059 within peripheral nerves after axonal injury, and the 14. Raman IM, Bean BP (1997) Resurgent Sodium Current and Ac- spontaneous discharge at these sites is thought to re- tion Potential Formation in Dissociated Cerebellar Purkinje Neu- sult from an accumulation of Na+ channels (Devor et rons. J Neurosci 17:4517–4526 al.1989).Further,thereisevidencethatspecificsubtypes 15. Rasband MN, Trimmer JS, Schwarz TL, Levinson SR, Ellisman + MH, Schachner M, Shrager P (1998) Potassium Channel Distri- of Na channels are involved, including PN1 and PN3. bution, Clustering, and Function in Remyelinating Rat Axons. + The Na channels accumulating at neuromas are co- J Neurosci 18:36–47 localized with ankyrinG (Kretschmer et al. 2002), and the increased levels of both proteins, may reflect dys- regulation of trafficking and/or turnover rates. As more information becomes available on the neurobiological Trafficking of Proteins mechanisms regulating ion channel biosynthesis, traf- ficking, and targeting, it will beinteresting toapply these principles to models of neuropathic pain. For example, Definition if some forms of neuropathic pain are a consequence Proteins are synthesized on ribosomes in the cell body, of altered Na+ channel trafficking, then therapeutic packaged into vesicles in the Golgi apparatus, and then strategies designed to disrupt or perturb the trafficking transported along cytoskeletal structuresto their final lo- 2502 Training by Quotas cation in the cell. The process of targeted transport is a high strength behavior, is likely to be an effective re- trafficking. inforcer. If programmedor scheduled carefully, it can  Peripheral Neuropathic Pain serve to enhance or reinforce exercise. To an inactive  Trafficking and Localization of Ion Channels person, one who moves relatively little, activity is unlikely to be reinforcing but rest or “time out” from activity is. In the context of pain management, rest or “time out” from activity and attention or encour- Training by Quotas agement of important others around the person (e.g. the therapist) usually suffice as reinforcers, when WILBERT E. FORDYCE programmed appropriately. Department of Rehabilitation, University of Washington School of Medicine, Seattle, WA, USA Baseline [email protected] Baseline is the starting point or rate (i.e. number of rep- etitions) at which the target behavior is occurring, e.g. Synonyms number of stepswalked beforeweakness, painorfatigue causes stopping. If the target behavior is not in the per- Exercise; quotas; contingency management son’s present repertoire, establishing it by teaching or “shaping” is indicated (Fordyce 1976). Definition Walking, performing selected exercises, engaging in ac- Training by quota describes methods for increasing ex- tivities intended to diminish reclining time and increas- ercise and activity level by use of the quota system, a ing activity are common targets for behavior change. form of contingency management based on behavioral Talking about pain, grimacing, asking for and / or taking science. The methods make use of sensitivity to our en- analgesics are less frequently targets for change and vironments to improve our state. Review of the theoret- should become so only with careful consideration of ical and conceptual backgroundcan be found in texts by appropriateness to the patient’s condition and with full Fordyce (1976, 1990). “How” to do it will be described. informed consent. PINPOINT the  behavior to be changed (i.e. specify in  movement cycles, walking-steps, exercise repeti- Quota tions), RECORD the pre-intervention rate of the behav- Once baseline performance is identified, set quotas to be ior and CONSEQUATE, i.e. spell out the rate of rein- appliedforeachtrial.Theinitialquotashouldbeapprox- 2 forcement and by whom, always with the patient’s in- imately 3 or ¿ of baseline, e.g. laps walked = 7, initial formed consent. quota = 4 or 5, baseline of an exercise repetition = 5, initial quota = 2 or 3. Initial quota level should be deter- Characteristics mined by confidence that it is an amount well within the patient’s current repertoire, ensuring successes at early The term chronic pain encompasses many conditions. trials. It is better to have too low an initial quota and be Increasing exercise and / or activity level is not indicated sure of success than too high and a risk of failure. Quotas for all of them. Evaluation of a problem of chronic pain are then incremented at a rate driven mainly by an as- (ideally a multi-disciplinary, multi-modal process) in- cending performance curve confidently expected to pro- dicating increased exercise or activity is clearly to the vide several early succeeding trials before initial base- patient’s benefit points to using these methods. Quota line is reached. In short, “success breeds success.” methods help patients increase exercise or activity lev- els. They are not methods for treating pain. Increases in Quota Increment Rates activity level help restore patient accessto activitiesusu- Most commonly, incrementing by 1 repetition per trial allyengagedin.Whentargetlevelsofactivityorexercise orsessionisappropriate.Incasesofmarginallyadequate are reached, the program can be faded to maintenance ability to increment, a slower rate (e.g. 1 × each 2 or 3 levels or stopped altogether. Re-entry into sustaining ac- trials) may suffice. An amount easily performed may in- tivitiesshould be achievedbeforehaltingorreducingex- dicate increments of 2 or more with each trial, but do ercise levels. that only if confident that several successful sessions are  Reinforcers are usually simple to define and ap- achieved prior to reaching baseline. In all cases, full in- ply in the practical case, using the Premack Principle formed consent prior to performance is indicated. Quota (Premack 1959). This states that high strength behav- increment rates should be spelled out to the patient fol- iors reinforce low strength behaviors; paraphrased as, lowing their determination, including the expected end- what a person does a lot of can be used to reinforce point. activities or movements targeted to be increased. Observing the consequences of what the person does Quota Endpoints a lot can usually readily identify effective reinforcers. Within physiological limits, quota endpoints or targets To a restless person frequently on the move, activity, are defined mainly by practical considerations. Target Trajectory 2503 levels must consider time to permit achieving current Quota quota levels, as well as overall fatigue considerations Usually one repetition per trial suffices. Increment rates if there is an array of exercises to be performed. Quota of >1 repetition per trial could be designated if there is increments and endpoints are also moderated by patient ample confidence that performance will succeed, partic- access to monitoring. For example, for a patient for ularly if access to monitoring is limited by the calendar. whom 3 weeks of daily trials is the logistical limit, quota endpoints may be limited by the time available to Consequate reach them using the quota increments selected, unless Rest or time out from the exercise, plus therapist atten- surrogate monitoring is available, e.g. family. tion and regard suffice. Examples Quota Failures (see also Fordyce 1976, 1990) Walking The options re failure divide into (a) problems of patient Pinpoint status and access and (b) performance. Lay out the course to be walked (e.g. a 25 m lap in a hos- Status pital corridor or distance in meters from the front door If opportunity to perform was not the problem, ask the of home to a selected landmark). patient why failure? If change in health or status of Baseline pain is the problem, clarify with the attending physi- cian whether to proceed with quotas, change exercises, The initial baseline should be within expected patient etc. Scheduling problems or access to equipment with tolerance. The patient is asked to walk laps (start-end- which to perform can be dealt with directly. return to start) until “pain,weaknessorfatigue cause you to want to stop. You decide when tostop.” If the patient is Performance unable to do at least one lap, shorten the lap distance un- Your value as a source of reinforcement should not be til two or more repetitions are within starting tolerance. expended carelessly. Admonitions or urging better per- Theoretically, baseline is defined by a stabilizing perfor- formance lets your attention become contingent on fail- mance curve. Usually, however, in the exercise context, ure. Instead, convey that you hope and expect he / she 2–3 baseline trials suffice. Each trial is spaced to provide will be able to resume meeting quotas and leave it at that. ample rest between trials. If on subsequent trials success is achieved, be quick to praise. Record If the patient is not invested in getting better, the patient Record laps walked each trial. A graph on the wall at should choosewhether to proceed or tohalttheprogram. the bedside or in a folder carried by the patient is ade- Discussions with significant others to the patient may quate. By making recorded results “visible”, an element also help. of social support or reinforcement is also provided. References Quota 1. Fordyce WE (1976) Behavioral methods in chronic pain and ill- T One lap increments per trial usually suffices. ness. C.V. Mosby, St. Louis, pp 236 2. Fordyce WE (1990) Contingency Management. In: Bonica JJ Consequate Management of Pain, vol 2, 2nd edn. Lea & Febiger, Philadel- Reinforcement from rest (i.e. time out from the activ- phia, pp 1702–1710 (also in: Bonica JJ (2001) Management of Pain, 3rd edn. Lippincott, Williams & Wilkins, Philadelphia, ity) and social approval of contextual personnel usually pp 1745–1750) suffice. Resort to some form of tangible reinforcement 3. Premack D (1959) Toward Empirical Behavior Laws: I Positive is rarely needed. See Fordyce (1976, 1990) for more on Reinforcement. Psychol Rev 66:219–233 this. Exercise: (e.g. Hip Abduction, Deep Knee Bends, Arm Exten- sion) Trait Pinpoint  The patient is asked to perform the assigned exercise (al- Personality and Pain ways with full informed consent) and instructed as to howtodoit. Baseline Trajectory The patient is asked to perform the assigned exercise Definition “until pain, weakness or fatigue cause you to want to stop. You decide when to stop.” Amounts performed The path of pain expression over time. across 2–3 trials, spaced appropriately, are recorded.  Pain Assessment in Neonates 2504 Tramadol

Tramadol is metabolized, via the CY2D6 isoenzyme of Tramadol cytochrome P450, to eleven metabolites of which only Definition O-desmethyltramadol (M1) is active. M1 has a greater affinity for opioid receptors and exerts greater analgesia Tramadol is a synthetic, centrally acting analgesic agent than tramadol. About 7%–8% of Caucasians lack this that is structurally related to codeine and morphine; it is isoenzyme. Tramadol has a half-life of about 6–7 hours a racemic mixture, and the 2 enantiomers function in a and is principally excreted via the kidneys. At least 30% complementary manner to enhance analgesic actions. It remains unchanged (Tramal 2004). also acts as a weak opioid agonist and inhibits the sero- tonin release and reuptake of norepinephrine and sero- Routes of Administration tonin. The analgesic effects of oral tramadol (100mg) Tramadol can be administered orally, rectally and par- peak at 1–2 hrs and last for 3–6 hours after drug admin- enterally.Forformulationsanddosingschedulesreaders istration. should consult the product information pertinent to their  Acute Pain in Children, Post-Operative respective jurisdictions.  Drugswith Mixed Action and Combinations, Empha- sis on Tramadol Applications  Post-Operative Pain, Tramadol The agent is indicated for the treatment of mild to mod-  Tramadol Hydrochloride erate pain. It is less effective than morphine for severe pain (Kaye 2004; Pang et al. 1999; Osipova et al. 1991). Tramadol Hydrochloride Efficacy When administered to post-surgical and post-traumatic JAYANTILAL GOVIND patients, 100 mg injectable tramadol is equivalent to Department of Anaesthesia, Pain Clinic, University of 5–10mg of morphine. As an oral dose, 100 mg tra- New South Wales, Liverpool Hospital, Sydney, NSW, madol is as effective as 1000 mg paracetamol (Moore Australia and McQuay 1997). For achieving 50% reduction of [email protected] pain, tramadol has an NNT of 4.6 (Moore and McQuay 1997). For 150 mg the NNT is 2.9 (Drugdex Drug Synonyms ® ® Evaluations. Micromedex Healthcare series). Tramadol; Tramal ; Zydol Tramadol has been shown to be effective for the relief of Definition neuropathicpain (Duhmke 2004). Patients with chronic An analogue of codeine, tramadol hydrochloride is a painful neuropathy reported relief of their pain, paraes- centrally acting analgesic. It is not derived from natural thesia and touch evoked allodynia by 2 median points on a10-pointscale(Sindrup1999).Toachievea50%reduc- sources, and structurally is not related to opioids; but  does exhibit certain opioid characteristics. tioninpainlevel,the NNT is between 3 and 6, using a daily dose of 200 mg – 400 mg. Studies investigating the Characteristics efficacy of tramadol for the treatment of pain of diabetes Mechanism neuropathy (Harati 1998) and  post-herpetic neuralgia Animal and in-vitro studies suggest that in addition to have been inconclusive (Wareham DW 2004). its mu-opioid effect, tramadol synergistically inhibits The safety and efficacy of tramadol in patients under the the reuptake of norepinephrine (NE) and serotonin, and age of 16 years has not been established (Drugdex Drug simultaneously stimulates the pre-synaptic release of Evaluations. Micromedex® Healthcare series). serotonin (Raffa and Fridericks 1996; Bamigbade et al. Contraindications 1997). It has a weak affinity for opioid receptors and is less potent than morphine. The analgesic effect is Tramadol is contraindicated in patients with: por- apportioned between the opioid and monoaminergic phyria; known hypersensitivity to tramadol, opioids or components (Desmoules et al. 1996). The response is any excipients; acute intoxication with alcohol, opioids, dose-dependent but the relationship between analgesic hypnotics, analgesics, or psychotropic drugs; who use effect and serum concentration varies considerably monoamine oxidase inhibitors, or have used them in between individuals. the last 14 days. Tramadol must not be used for opi- oid dependency, addiction or for opioid withdrawal Pharmacokinetics treatment (Kaye 2004; Pang et al. 1999; Drugdex Drug After oral administration, tramadol israpidly andalmost Evaluations. Micromedex® Healthcare series). completely absorbed with a mean bio-availability of 68%–72%. The drug is widely distributed and 20% Side effects and complications is bound to plasma proteins. The peak serum level is Adverse reactions are common and patients must be reached within two hours (range 1–3 hours) (Tramal given guidance about appropriate action. The potential 2004). for serious side effects including anaphylaxis should Tramadol Hydrochloride 2505 not be underestimated. Either the monoaminergic or Precautions opioid effects may predominate. The adverse effects Tramadol is best avoided in patients with epilepsy, and of tramadol may be difficult to distinguish or recog- in patients who are at risk of developing respiratory nize in patients taking multiple medications. Even with depression. Because of miosis and its central effects, therapeutic doses opioid side-effects can occur, except it is inadvisable to prescribe tramadol for patients with respiratory depression and inhibition of smooth mus- a head injury or raised intracranial pressure. Elderly cle, which are usually less pronounced (Kaye 2004; patients and patients with renal or hepatic decompen- ® Drugdex Drug Evaluations. Micromedex Healthcare sation, myxoedema, hypothyroidism, hypoadrenalism series). are particularly vulnerable to severe side effects and Central effects include seizures, hallucinations, eupho- complications. Its administration may complicate the ria, ataxia, and suicidal ideation. Co-administration clinical assessment of patients with acute abdominal with alcohol, general anaesthetics, or other respiratory conditions (Kaye 2004; Drugdex Drug Evaluations. depressants can precipitate profound respiratory de- Micromedex® Healthcare series). compensation. Dizziness can cause at-risk patients to fall. Pregnancy and lactation Gastrointestinal side effects are very common, includ- Tramadol has been detected in breast milk. It is best ing nausea, vomiting, and constipation. Dyspepsia, diar- avoided during pregnancy and whilst breast-feeding rhoea and increased flatulence have been reported(Kaye (Kaye 2004). 2004). Although uncommon, cardiovascular side-effects such Overdose as hypertension, palpitations, tachycardia, bradycardia, Treatment is symptomatic. The effects are not com- other ECG abnormalities, and orthostatic dysregulation pletely reversed by naloxone (Kaye 2004), and the do occur and can be serious. latter may increase the risk of seizure (Drugdex Drug Additional reported side effects include urinary reten- Evaluations. Micromedex® Healthcare series). tion, erythema, hypertonia, hyponatraemia, itch, rhab- domyolysis and diaphoresis. References 1. Raffa RB, Fridericks E (1996) The basic science aspect of tra- Drug interactions madol hydrochloride. Pain Rev 3:249–271 Tramadolisknowntointeractwithatleast72otherdrugs, 2. Bamigbade TA, Davidson C, Langdord RM, Stamford JA (1997) Actions of tramadol: its enantiomers and principle metabolite, some with serious consequences (Kaye 2004; Drugdex O-desmethyltramadol on serotonin (5-HT) efflux and uptake in ® Drug Evaluations. Micromedex Healthcare series). the rat dorsal raphe nucleus. Br J Anaesth 79:352–356 Carbamazepine reduces tramadol’s analgesic effect by 3. Desmoules JB, Piquet R, Collart L, Dayer P (1996) Combination increasing its metabolism. Drugs that inhibit CY2D6 of monoaminergic modulation to the analgesic effect of tramadol Br J Clin Pharmacol 41:7–12 activity (e.g. Selective Serotonin Reuptake Inhibitors 4. Tramal (2004) Product information. CSL Limited. Parkville, [SSRI], or quinidine) will prevent conversion to its VIC, Australia active metabolite, M1. 5. Kaye K (2004) Trouble with tramadol (editorial) Australian Pre- T Serotonin syndrome is a potentially serious toxic scriber 27:26–27 6. Pang, WW, Mok MS, Lin CH, et al. (1999) Comparison of patient state caused mainly by excess serotonin within the controlled analgesia (PCA) with tramadol or morphine. Can J central nervous system (Hall and Buckley 2003). It Anesth 46:1030–1035 manifests as a dose-related range of toxic symptoms 7. Osipova NA, Novikov GA, Beresnev VA et al. (1991) Analgesic effect of tramadol in cancer patients with chronic pain: a com- due to a variety of mental, autonomic and neuro- parison with prolonged action morphine sulfate. Curr Ther Res muscular changes. The clinical features are highly 50:812–821 variable and the onset could be insidious or dra- 8. Moore RA, McQuay HJ (1997) Single-patient data meta-analysis matic. It is nearly always caused by a drug inter- of 3453 postoperative patients: oral tramadol versus placebo, action involving two or more ‘serotonergic’ drugs codeine and combination analgesics. Pain 69:287–294 9. Drugdex Drug Evaluations. Micromedex® Healthcare se- including SSRIs, MAOI, pethidine, tricyclic antide- ries.  http://micromedex.hen.net.au/mde-3261/display.exe pressants, St John’s wort and lithium. Severe hyper- CTL=apache/products/micromede. Accessed 13.10.04 thermia, rhabdomyolysis, disseminated intravascular 10. Duhmke RM, Cornblath DD, Hollingshead JR (2004) Tramadol for neuropathic pain. Cochrane Database Syst Rev: CD003726 coagulation and adult respiratory distress syndrome 11. Sindrup SH, Andersen G, Madsen C, Smith T, Brosen K, Jensen are potentially life-threatening (Hall and Buckley TS (1999) Tramadol relieves pain and allodynia in polyneuropa- 2003). thy: a randomised double blind controlled trial. Pain 83:85–90 12. Harati Y, Gooch C, Swenson M et al. (1998) Double blind ran- domized trial of tramadol for the treatment of the pain of diabetic Reproduction neuropathy. Neurology 50:1842–1846 Tramadol is embryotoxic and fetotoxic but not tetrato- 13. Wareham DW (2004) Postherpetic Neuralgia. In: Godlee F (ed) Clinical Evidence. edn genic in animal studies (Drugdex Drug Evaluations. 14. Hall M, Buckley N (2003) Serotonin Syndrome. Australian Pre- Micromedex® Healthcare series). scriber 26:62–63 2506 Tramal¨

Definition Tramal® Transcutaneous electrical nerve stimulation (TENS) is a meansof relieving pain. It entailsdelivering an electrical  Postoperative Pain, Tramadol stimulus through electrodes to the skin overlying or near  Tramadol Hydrochloride the region in which pain is perceived. The stimulus is delivered from a battery-driven generator. Characteristics Transcranial Magnetic Stimulation TENS is a commonly used non-invasive modality that provides an alternative to medication for pain relief. It hasbeenusedformorethan30years,butitseffectiveness Synonyms remains controversial. TMS Mechanism TENS was developed on the basis of the gate control Definition theory of pain proposed by Melzack and Wall (Melzack Transcranial Magnetic Stimulation refers to stimulation andWall1965).Thistheorypredictedthatstimulationof of the cerebral cortex by an electromagnetic field, gener- large-diameter primary afferent fibres (A fibres) would ated by a magnetic stimulator placedover the scalp with- have an inhibitory effectontransmission fromthesmall- out the need for surgery or externalelectrodes. Magnetic diameter, unmyelinated afferent fibres (C fibres). Ac- stimuli can also activate the peripheral nervous system. cordingly, pain should be relieved if cutaneous afferents  Clinical Migraine without Aura from a region of pain could be artificially stimulated us-  Motor Cortex, Effect on Pain-Related Behavior ing an electrical current.  Stimulation Treatments of Central Pain A battery-operated, transistorised unit generates the electrical stimulus. There are usually three separate controls. The first varies the amplitude or intensity, and allows for administration of a range from low (2–4Hz) to high (100–250 Hz) frequency stimulation. Transcription Factor A second varies pulse width, usually from 0.04-0.1 ms, and a third controls the mode to select continuous or Definition pulsed ± ramped, ± random stimulus. The stimulus is delivered through pads attached to the skin surface. The A protein, product of gene transcription and translation, electrical field generated has to be of sufficient magni- which enters the nucleus where it binds to a nucleotide tude to excite the adjacent afferent nerve fibres without sequence in the regulatory regions of responsive genes, damaging the local skin, producing dysaesthesia or and has the effect of either enhancing or repressing the producing painful muscle contractions. expressionofoneormoregenesdownstreamofthebind- The mechanism of action of TENS has not been explic- ing site. Expression of one gene is normally controlled itly or directly demonstrated. However, it is believed by several transcription factors. that low frequency stimulation releases mu opioids (β-  Central Changes after Peripheral Nerve Injury endorphins), while high frequency stimulation releases  COX-1andCOX-2inPain delta opioids (met-enkephalin and leu-enkephalin) in  Cytokines, Effects on Nociceptors the central nervous system. The mu receptor antago-  NSAIDs and Cancer nist – naloxone, inhibits the effects of low frequency stimulation, but not those of high frequency stimulation (Sjolund and Eriksson 1979; Freeman et a. 1983). Rats develop opioid tolerance after 4 days when treated with Transcutaneous Electrical Nerve TENS for 20 min. a day (Chandran and Sluka 2003). Stimulation Due to the development of tolerance, treatment is more effective when TENS is used intermittently. Daily ad- JAMES WATT ministration lessens the analgesic effect. The short du- North Shore Hospital, Auckland, New Zealand rationofbenefit(260minutes)(Cheingetal.2003),how- [email protected] ever, encourages frequent application in chronic condi- tions; but this in turn reduces pain relief. Synonyms Applications TENS; AL-TENS (Acupuncture like TENS); Electrical TENS is used for the control of pain of various types in Therapy. various regions of the body. The portability, safety and Transcutaneous Electrical Nerve Stimulation 2507 low cost of the transistorised impulse generator have all reviewed 21 randomised placebo-controlled trials with contributed to its wide and varied use in the field of pain a total of 1350 patients, and demonstrated a mean reduc- medicine. tion in analgesic consumption after TENS/AL-TENS A number of factorsneedtobeconsideredwhenoffering of 26.5% (range –6 to +51%). Eleven of these trials, cov- TENS as a treatment option. The aim is to produce the ering 964 patients, reported that a strong sub-noxious optimal tolerable stimulus. Application is critical to the electrical impulse of adequate stimulus frequency was success of the treatment. The site of stimulation should administered. These trials demonstrated a reduction be chosen to produce maximal input in the segment in analgesic consumption of 35.5% (range 1–51%). In where the pain originates, and should be proximal to it. comparison, theninetrialsthatdidnotconfirmsufficient It is often not possible to predict the optimal placement current intensity or adequate frequency, demonstrated or type of electrodes, or the stimulus that will produce a reduction of only 4.1% (range –10 to +29%). maximal pain relief. Consequently, with guidance, the The short-term analgesic efficacy of TENS was demon- patient should be encouraged to experiment with am- strated in a trial using distension arthrography (a moder- plitude, frequency and pulse width, as well as electrode ately painful procedure) for frozen shoulder. There was placement and duration of stimulus, in order to maxi- a50%reduction using high intensity TENS, and38%re- mize their relief of pain. Most choose frequencies from duction using low intensity TENS, compared to controls 40–70 Hz; with a pulse-width of 0.1–0.5 ms. Stimu- (Morgan et al. 1996). lation at lower frequencies requires higher intensity Thus, the evidence is mixed. This is due, in part, to the of stimulus, which tends to produce painful muscle poor quality of studies available, and the lack of clear contractions. definition of the treatment given. The effect has been Maximal comfortable stimulus is more effective in re- showntodifferdependingonanumberofvariablesinthe lieving pain than stimulation that is barely detectable. treatmentapplication.Thesearefrequency,intensityand However, the theoretical argument of providing a suffi- waveform of the stimulus, site and duration of its appli- ciently powerful stimulus to activate both small myeli- cation, and conduction medium. All need to be recorded nated A-delta fibres and large A-beta fibres is negated clearlyforeverysubjectinatrialoftheefficacyofTENS. by the difficulty patients have in tolerating continuous Side-Effects high-intensity stimulation. Opioid tolerance can develop with repeated daily use. Efficacy There are few other side effects from the administration Two Cochrane reviews, one of chronic pain (Carroll et of TENS, probably due to the application generally al.2002),andtheotherofchroniclowbackpain(Milneet being under the patient’s control. There is the theo- al. 2002), demonstrate lack of effectiveness. There were retical risk that too high a stimulus could damage the wide variations in the parameters of type, site and fre- skin by electrical burn, but it is unusual for patients to quency of application, treatment duration, intensity and achieve such damage. The range of machine settings, frequency of the electrical impulse in both reviews. and the noxious stimulus produced by painful muscle Many studies show lack of evidence of benefit. There contraction at the higher stimulus range, affords pro- was no evidence that TENS was any more effective than tection. Side effects really only occur in the presence T other conservative treatments for acute and chronic non- of excessive zeal. specific low back pain (van Tulder et al. 1997) or for  Acupuncture Mechanisms chronic pain (McQuay e al. 1997). TENS was found  Chronic Pain in Children, Physical Medicine and Re- not to be effective in relieving labour pain (Carroll et habilitation al. 1997).  Complex Chronic Pain in Children, Interdisciplinary In contrast, a Cochrane Review by Proctor (Proctor et Treatment al.2002)showedhighfrequencyTENStobemoreeffec-  McGill Pain Questionnaire tive than placebo in relieving primary dysmenorrhoea,  Pain in Humans, Electrical Stimulation (Skin, Muscle while low frequency TENS showed no difference. A and Viscera) review by Osiri (Osiri et al. 2001) on knee osteoarthritis  Postoperative Pain, Appropriate Management showed TENS provided significantly better pain relief  Transcutaneous Electrical Nerve Stimulation Out- and improved movement, compared with placebo. The comes effect had previously been shown in three randomised  TranscutaneousElectricalNerveStimulation(TENS) controlled trials reviewed in a paper by Puett and Grif- in Treatment of Muscle Pain fin (Puett and Griffin 1994). However, Osiri’s review showed that TENS only differed from placebo when References treatment continued for more than 4 weeks in duration. 1. Bjordal JM, Johnson MI, Ljunggreen AE (2003) Transcutaneous The efficacy of TENS in acute situations is attested in Electrical Nerve Stimulation (TENS) can Reduce Postoperative Analgesic Consumption. A Meta-Analysis with Assessment of a meta-analysis of studies of reduction of analgesic use Optimal Treatment Parameters for Postoperative Pain. Eur J in post-operative patients. Bjordal (Bjordal et al. 2003) Pain 7:181–188 2508 Transcutaneous Electrical Nerve Stimulation (TENS) in Treatment of Muscle Pain

2. Carroll D, Moore RA, McQuay HJ, Fairman F, Tramer M, Leijon G (2002) Transcutaneous Electrical Nerve Stimulation (TENS) for Chronic Pain (Cochrane Review). The Cochrane Library, Is- sue 2 3. Carroll D, Moore RA, Tramer MR, McQuay HJ (1997) Transcu- taneous Electrical Nerve Stimulation Does Not Relieve Labour Pain: Updated Systematic Review. Contemporary Reviews in Ob- stetrics and Gynaecology: 195–205 4. Chandran P, Sluka KA (2003) Development of Opioid Tolerance with Repeated Transcutaneous Electrical Nerve Stimulation Ad- ministration. Pain 102(1–2):195–201 5. Cheing GL, Tsui AY,Lo SK, Hui-Chan CW (2003) Optimal Stim- ulation Duration of TENS in the Management of Osteoarthritic Knee Pain. J Rehabil Med 35(2):62–68 Transcutaneous Electrical Nerve Stimulation (TENS) in Treatment of 6. Freeman TB, Campbell JN, Long DM (1983) Naloxone Does Muscle Pain, Figure 1 An electrical pulse generator delivers currents via Not Affect Pain Relief Induced by Electrical Stimulation in Man. conducting electrodes attached to the intact surface of the skin. Tradition- Pain 17:189–195 ally, carbon rubber electrodes smeared with conducting gel and attached 7. McQuay HJ, Moore RA, Eccleston C, Morley S, DeC Williams to the skin using self-adhesive tape were used to deliver the electrical AC (1997) Systematic Review of Outpatient Services for Chronic currents. Nowadays, self-adhesive electrodes are used. Pain Control. Health Technology Assessment 1(6):1–137 8. Melzack R, Wall PD (1965) Pain Mechanisms: A New Theory. Science 15:971–979 9. Milne S, Welch V, Brosseau L, Saginur M, Shea B, Tugwell Definition P, Wells G (2002) Transcutaneous Electrical Nerve Stimulation  (TENS) for Chronic Low Back Pain (Cochrane Review). The Transcutaneous electrical nerve stimulation (TENS) Cochrane Library, Issue 1 is a non-invasive analgesic intervention, which delivers 10. Morgan B, Jones AR, Mulcahy KA, Finlay DB, Collett B electrical currents across the intact surface of the skin (1996) Transcutaneous Electrical Nerve Stimulation (TENS) to stimulate the underlying nerves (see Fig. 1). TENS is during Distension Shoulder Arthrography: A Controlled Trial. Pain 64:265–267 used extensively for the symptomatic relief of all types 11. Osiri M, Welch V, Brosseau L, Shea B, McGowan J, Tugwell P, of pain, including pains of musculoskeletal origin. Wells G (2001) Transcutaneous Electrical Nerve Stimulation for The purpose of TENS is to activate selectively those Knee Osteoarthritis (Cochrane Review). The Cochrane Library, populations of nerve fibres that are concerned with Issue 1   12. Proctor ML, Smith CA, Farquhar CM, Stones RW (2002) Tran- segmental and extrasegmental anti-nociceptive scutaneous Electrical Nerve Stimulation and Acupuncture for mechanisms. The two main TENS techniques are Primary Dysmenorrhoea (Cochrane Review). The Cochrane Li-  conventional TENS and  acupuncture-like TENS brary, Issue 1 (AL-TENS). 13. Puett DW, Griffin MR (1994) Published Trials of Non-Medicinal and Non-Invasive Therapies for Hip and Knee Osteoarthritis. Ann Int Med 121:133–140 Characteristics 14. Sjolund BH, Eriksson MBE (1979) The Influence of Naloxone on Analgesia Produced by Peripheral Conditioning Stimulation. TENS is popular because patients can administer TENS Brain Res 173:295–301 themselves and can titrate the dosage of treatment as 15. van Tulder MW, Koes BW, Bouter LM (1997) Conservative required. TENS effects are often rapid in onset and Treatment of Acute and Chronic Non-Specific Low Back Pain: A Systematic Review of Randomised Controlled Trials of the there are few side effects and no potential for toxicity or Most Common Interventions. Spine 22:2128–2156 overdose. The technical specifications of TENS devices vary according to manufacturer, although most utilise biphasic pulsed currents that may be either symmetrical or non-symmetrical square waves. Pulse durations lie between 50 μs–1000 μs, pulse frequencies between Transcutaneous Electrical Nerve 1–200 pulses per second (pps) and pulse amplitudes be- Stimulation (TENS) in Treatment of tween 1–60 mA. Most devices offer continuous, burst Muscle Pain (used for AL-TENS) and modulated pulse patterns. Factors that influence the success of TENS include the MARK I. JOHNSON patient, the condition and the appropriateness of the Faculty of Health, Leeds Metropolitan University, TENS technique employed (see Fig. 2). Leeds, UK TENS is commonly used to treat chronic pains, includ- [email protected] ing those of musculoskeletal origin. Systematic reviews on TENS and chronic pain have been inconclusive due to the low methodologicalquality of RCTs (Reeve et al. Synonyms 1996; McQuay and Moore 1998; Carroll et al. 2003). Transcutaneous Nerve Stimulation (TNS); Transcuta- However, meta-analyses have demonstrated that TENS neous Electrical Stimulation; (TES) Electrical Stimu- is beneficial for knee osteoarthritis (Osiri et al. 2000) lation Therapy (EST); Percutaneous Electrical Nerve and rheumatoid arthritis in the hand (Brosseau et al. Stimulation; Electroanalgesia 2003). Meta-analysis on TENS for low back pain are Transcutaneous Electrical Nerve Stimulation (TENS) in Treatment of Muscle Pain 2509

Transcutaneous Electrical Nerve Stimulation (TENS) in Treatment of Muscle Pain, Figure 2 The output characteristics of a typical TENS device (topographic view). The amplitude, frequency, duration and pattern of electrical pulses can be controlled by the end user (I, intensity; F, frequency; D, duration; C, continuous; B, burst; M, modulation; pps, pulses per second). conflicting (Flowerdew and Gadsby 1997; Brosseau et al. 2002). Under dosing of TENS and the use of inappropriate TENS techniques in some RCTs have influenced the findings of systematic reviews (Bjordal et al. 2003). There have been no systematic reviews on TENS and muscle pain because of a lack of randomised controlled clinical trials. TENS is used extensively for reducing lo- calised muscle pain, especially in the neck and shoulder, arising from muscle tension. TENS is also used to treat acute traumatic muscle pain that results from physical injury from sport and minor accidents, and to treat post- exertional muscle pain. Reports suggest that TENS is Transcutaneous Electrical Nerve Stimulation (TENS) in Treatment of helpful for myofascial pain syndrome (Graff-Radford et Muscle Pain, Figure 3 The purpose of conventional TENS is to activate non-nociceptive cutaneous afferents (Aβ) without concurrent activation no- al.1989;Houetal.2002)andlocalisedpaininfibromyal- ciceptive (Aδ/C) or muscle afferents. Arrows indicate impulses travelling gia(Offenbacher and Stucki2000), althoughin practice, towards the central nervous system. T TENS reduces pain in some of these patients and aggra- vates it in others. It is unlikely that TENS will be helpful in widespread pain in fibromyalgia, because it isdifficult During conventional TENS electrodes are applied to to direct TENS currents into the painful area. healthy skin, at the site of pain, to stimulate large diame- In clinical practice, conventional TENS is used in the ter non-nociceptive cutaneous afferents which enter the first instance for most pains, including those of muscu- same spinal segment as the nociceptive fibres associated loskeletal origin. The purpose of conventional TENS is with the origin of the pain. When it is not possible to to activate selectively large diameter non-nociceptive apply electrodes at the site of pain, for example when cutaneous afferents (Aβ) without concurrently activat- the skin is damaged and/or sensitive to touch, electrodes ing small diameter nociceptive afferents (Aδ and C), can be applied proximally over the main nerve trunk which would cause pain, or muscle efferents, which that innervates the skin at the site of pain. Alternatively, would cause muscle contractions. TENS-induced Aβ electrodes can be placed over the spinal cord at a level activity has been shown to inhibit ongoing activity in segmentally related to the site of origin of the pain, or second order nociceptive neurones in the dorsal horn of at a site which is contralateral (mirror image) to the site the spinal cord (Garrison and Foreman 1994). In prac- of pain. Dual channel devices using 4 electrodes can be tice, large diameter non-nociceptive cutaneous afferent used for pains covering large areas such as in a gluteal activity is recognised by a ‘strong but comfortable’ non- region or lower limb, and for multiple pains such as low painful electrical paraesthesia beneath the electrodes, back pain and sciatica (see Fig. 4). and patients are trained to titrate current amplitude to For conventional TENS, maximum pain relief is achieve this outcome (see Fig. 3). achieved when the TENS device is switched on. There- 2510 Transcutaneous Electrical Nerve Stimulation (TENS) in Treatment of Muscle Pain

Transcutaneous Electrical Nerve Stimulation (TENS) in Treatment of Muscle Pain, Figure 4 (a) Electrode positions for common pain conditions – anterior view. (b) Electrode positions for common pain conditions – posterior view. fore, patients should be encouraged to use conventional TENS whenever the pain is present, although it is wise to instruct the patient to monitor their skin condition under the electrodes on a regular basis, and perhaps take regular (although short) breaks from stimulation. Dosing regimens of 20 minutes at daily, weekly or monthly intervals is likely to be ineffective for con- ventional TENS. Some patients report post-stimulation analgesia following conventional TENS, although re- ports of the duration of this effect varies widely and may reflect natural fluctuations in symptoms rather than specific TENS-induced effects. The relationship Transcutaneous Electrical Nerve Stimulation (TENS) in Treatment of between the pulse frequency, duration and pattern of Muscle Pain, Figure 5 The purpose of AL- TENS is to elicit a non painful TENS and the magnitude of analgesia for different pain muscle twitch by activating large diameter motor efferents. The muscle twitch generates activity in ergoreceptors and small diameter group III (GIII) conditions has not been fully confirmed in the clini- muscle afferents which initiates extrasegmental antinociceptive mecha- cal setting as much available evidence is conflicting, nisms. Aβ afferents may also become active as currents pass through the inconclusive or methodologically flawed. Encour- skin. Arrows indicate direction of relevant impulse information. aging patients to experiment with all TENS settings while they maintain a strong but comfortable electrical paraesthesia within the site of pain may be the most effective approach for conventional TENS (Johnson trigger points. However, some patients report that that 2001). this aggravates their pain. In such circumstances AL- AL-TENS is a variant of conventional TENS and has TENScanbeadministeredonthecontralateralmyotome been successfully used for pains of musculoskeletal ori- (Sjölund et al.1990; Johnson 1998) (see Fig. 5). gin. The purpose of AL-TENS is to stimulate axons of AL-TENS is administered over muscles and motor muscle efferent neurons (α motor axons) to generate a points using low frequency burst patterns of pulse de- forcefulbutnon-painfulphasicmuscletwitch.Thismus- livery. Currents are delivered at high but non-painful cle twitch generates activity in small diameter Group intensities, to generate a forceful but non-painfulphasic III muscle afferent neurons, which trigger extrasegmen- muscle twitch. Currents delivered during AL-TENS tal anti-nociceptive mechanisms, which lead to the re- will also activate Aβ fibers during their passage through lease of opioid peptides in a manner similar to that sug- the skin leading to segmental analgesia. AL-TENS gested for acupuncture. AL-TENS is helpful for radiat- is administered intermittently for 20–30 minutes at a ing neurogenic pain and forpatientswhohave decreased time to reduce excessive muscle fatigue. The general skin sensitivity from damage to cutaneous afferents in impression of users is that post-TENS analgesia is thepainfulregion.AL-TENShasbeenusedsuccessfully longer for AL-TENS than conventional TENS, and this for muscle pain by stimulating the painful muscles and is supported by initial findings in experimental studies. Transcutaneous Electrical Nerve Stimulation Outcomes 2511

For this reason, AL-TENS is useful for patients who obtain brief after-effects from conventional TENS, or Transcutaneous Electrical Nerve who are resistant to conventional TENS. Stimulation Outcomes TENS should not be administered to patients fitted with MARK I. JOHNSON cardiac pacemakers or women in the first trimester of School of Health and Human Sciences, Faculty of pregnancy. TENS should not be used while operating Health, Leeds Metropolitan University, Leeds, UK vehicles or potentially hazardous equipment, and elec- [email protected] trodes should not be positioned over the anterior part of the neck, over areas of broken skin or directly over Synonyms a pregnant uterus (although it is safe when applied to the lower back to treat labour pains). Patients should be TENS Outcomes; transcutaneous nerve stimulation; testedfornormalskinsensationpriortousingTENS.Pa- TNS; transcutaneous electrical stimulation (TES); tients should be warned not to use TENS in the shower electrical stimulation therapy (EST); Percutaneous or bath and to keep TENS appliances out of the reach of Electrical Nerve Stimulation; Electroanalgesia children. Definition  Transcutaneous electrical nerve stimulation (TENS) References is a non-invasive analgesic intervention that deliv- 1. Bjordal JM, Johnson MI, Ljunggreen AE (2003) Transcutaneous ers electrical currents across the intact surface of Electrical Nerve Stimulation (TENS) can Reduce Postoperative the skin to stimulate the underlying nerves. TENS Analgesic Consumption. A Meta-Analysis with Assessment of is used extensively for the symptomatic relief of all Optimal Treatment Parameters for Postoperative Pain. Eur J Pain 7:181–188 types of pain including pains of nociceptive, neuro- 2. Brosseau L, Milne S, Robinson V et al. (2002) Efficacy of the pathic and musculoskeletal origin. The purpose of Transcutaneous Electrical Nerve Stimulation for the Treatment TENS is to activate selectively those populations of of Chronic Low Back Pain: A Meta-Analysis. Spine 27:596–603 nerve fibres that are concerned with segmental and 3. Brosseau L, Yonge KA, Robinson V et al. (2003) Transcuta- neous Electrical Nerve Stimulation (TENS) for the Treatment extrasegmental anti-nociceptive mechanisms. The two of Rheumatoid Arthritis in the Hand (Cochrane Review). The main TENS techniques are  conventional TENS and Cochrane Library Oxford: Update Software Issue 3:1–19  acupuncture-like TENS (AL-TENS). 4. Carroll D, Moore RA, McQuay HJ et al. (2003) Transcutaneous Electrical Nerve Stimulation (TENS) for Chronic Pain. In: The Characteristics Cochrane Library, Issue 3. Update Software, Oxford 5. Flowerdew M, Gadsby G (1997) A Review of the Treatment Clinical experience supports a role for TENS in the of Chronic Low Back Pain with Acupuncture-Like Transcuta- management of acute and chronic pain. Clinical re- neous Electrical Nerve Stimulation and Transcutaneous Electri- cal Nerve Stimulation. Complement Ther Med 5:193–201 search on TENS also reports beneficial effects for a 6. Garrison DW, Foreman RD (1994) Decreased Activity of Sponta- wide range of chronic pain conditions including back neous and Noxiously Evoked Dorsal Horn Cells during Transcu- pain, neck pain, headache, osteoarthritis, rib fracture, taneous Electrical Nerve Stimulation (TENS). Pain 58:309–315 orofacial pain, post-herpetic neuralgia, trigeminal neu- 7. Graff-Radford SB, Reeves JL, Baker RL et al. (1989) Effects T of Transcutaneous Electrical Nerve Stimulation on Myofascial ralgia, post-stroke pain, phantom limb and stump pain, Pain and Trigger Point Sensitivity. Pain 37:1–5 brachial plexus avulsion, causalgia, angina pectoris, 8. Hou CR, Tsai LC, Cheng KF et al. (2002) Immediate Effects of myalgia, postoperative pain, labour pain, dental pain Various Physical Therapeutic Modalities on Cervical Myofas- and cancer pain (Hansson and Lundeberg 1999). How- cial Pain and Trigger-Point Sensitivity. Arch Phys Med Rehabil 83:1406–1414 ever, many clinical trials lack appropriate controls 9. Johnson M (1998) The Analgesic Effects and Clinical Use of and / or randomisation leading to overestimation of Acupuncture-Like TENS (AL-TENS). Phys Ther Rev 3:73–93 treatment effects. In recent years, systematic reviews 10. Johnson MI (2001) Transcutaneous Electrical Nerve Stimula- tion. In: Kitchen S (ed) Electrotherapy: Evidence-Based Practice. and meta-analyses have challenged the effectiveness of Churchill Livingstone, Edinburgh, pp 259–286 TENS. 11. McQuay H, Moore A (1998) TENS in Chronic Pain. In: McQuay Many clinical trials on TENS and chronic pain suffer H, Moore A (eds) An Evidence-Based Resource for Pain Relief. methodological inadequacies and fail to meet the inclu- Oxford University Press, Oxford, pp 207–211 12. Offenbacher M, Stucki G (2000) Physical Therapy in the Treat- sion criteria for systematic reviews. Systematic review- ment of Fibromyalgia. Scand J Rheumatol 113:78–85 ers report that the lack of good quality RCTs makes it 13. Osiri M, Welch V, Brosseau L et al. (2003) Transcutaneous difficult to estimate the effectiveness of TENS. Reeve Electrical Nerve Stimulation for Knee Osteoarthritis. In: The et al. reported that TENS was more effective than sham Cochrane Library, Issue 3. Update Software, Oxford 14. Reeve J, Menon D, Corabian P (1996) Transcutaneous Electri- (dummy) TENS or no treatment in 9 / 20 RCTs on a cal Nerve Stimulation (TENS): A Technology Assessment. Int variety of chronic pain conditions (Reeve et al. 1996). J Technol Assess Health Care 12:299–324 McQuay et al. reported that TENS was better than sham 15. Sjölund B, Eriksson M, Loeser J (1990) Transcutaneous and Im- TENS, placebo pills or inappropriate electrode place- planted Electric Stimulation of Peripheral Nerves. In: Bonica JJ (ed) The Management of Pain, vol 2. Lea & Febiger, Philadel- ments in 10 / 24 RCTs on chronic pain (McQuay and phia, pp 1852–1861 Moore 1998). A follow-up review identified 107 reports 2512 Transcutaneous Electrical Nerve Stimulation Outcomes

Transcutaneous Electrical Nerve Stimulation Outcomes, Table 1 Physical Medicine, TENS outcomes Ref. Patients Results Reviewers’ Conclusion

Reeve et al. (1996) Mixed conditions (low back, pancreatitis, TENS >control in 9 / 20 RCTs Evidence arthritis, angina) inconclusive

McQuay and Moore Mixed conditions (low back, pancreatitis, TENS >control in 10 / 24 RCTs Evidence (1998) osteoarthritis, dysmenorrhoea) inconclusive

Carroll et al. (2003) Mixed conditions (low back, pancreatitis, TENS >control in 10 / 15 RCTs Evidence osteoarthritis, dysmenorrhoea) inconclusive

Flowerdue and Low back pain 288 patients (6 RCTs) Evidence of effect Gadsby (1997) TENS >sham for pain relief (OR = 2.11)

Brosseau et al. Low back pain 421 patients (5 RCTs) Evidence of no (2002) TENS = sham for pain relief (SMD = -0.207) effect

Price and Pandyan Post-stroke shoulder pain 170 patients (4 RCTs). Any surface electrical Evidence (2001) stimulation (ES) inconclusive ES = sham / no treatment control for pain relief (WMD = 0.13) ES >sham / no treatment control for range of movement (WMD = 9.17)

Proctor et al. (2002) Primary dysmenorrhoea 213 patients (8 RCTs) Evidence of HF TENS >sham for pain relief (OR = 7.2) effect – HF TENS LF TENS = sham for pain relief (OR = 1.3) only

Brosseau et al. Rheumatoid arthritis of the hand 78 patients (3 RCTs) Evidence of effect (2003) AL-TENS reduced pain at rest (67% relative benefit versus placebo)

Osiri et al. (2003) Knee osteoarthritis 294 patients (7 RCTs) Evidence of effect TENS >sham for pain relief (SMD = -0.448 – although only 2 / 7 RCTs +ve)

Abbreviations: RCT, randomised controlled clinical trial; OR, odds ratio; SMD, standardised mean difference; WMD, weighted mean difference; +ve, positive outcome; HF, high frequency; LF, low frequency on TENS and chronic pain but only 19 met the inclusion sion per week for 3 weeks. A meta-analysis of TENS criteria (Carroll et al. 2003). TENS provided better pain for primary dysmenorrhoea found that high frequency reliefthanshamornotreatmentcontrolsin10/15RCTs. but not low frequency TENS was more effective for Evidence for TENS effectiveness in specific chronic pain relief than sham TENS (Proctor et al. 2003). A pain conditions is also inconclusive or discordant. A meta-analysis of any form of surface electrical stimu- meta-analysis of 288 low back pain (LBP) patients (6 lation (ES) on 170 patients with post-stroke shoulder RCTs) found that TENS reduced pain and improved pain found no significant change in pain incidence or the range of motion (Flowerdew and Gadsby 1997). In pain intensity after ES compared with control (Price contrast, a meta-analysis of 321 LBP patients (5 RCTs) and Pandyan 2001). ES was reported to improve the found no statistically significant differences between pain-free range of passive humeral lateral rotation and active and sham TENS for pain relief (Brosseau et al. reduce the severity of glenohumeral subluxation. In 2002). A meta-analysis of 294 patients (7 RCTs) with summary, the effectiveness of TENS on chronic pain knee osteoarthritis found that TENS produced statis- remains uncertain. tically significantly more pain relief and reductions The effectiveness of TENS in reducing labour pain has in knee stiffness than placebo (Osiri et al. 2003). A been challenged by systematic reviews. TENS did not meta-analysis of 78 patients (3 RCTs) with rheuma- improve pain relief when compared to sham TENS or a toid arthritis of the hand found that AL-TENS reduced no treatment control in 3 / 8 RCTs (Reeve et al. 1996) pain intensity whereas conventional TENS did not, and 10 / 10 RCTs (Carroll et al. 1997). These systematic although conventional TENS improved the patient’s reviews seem to conflict with clinical experience where assessment of their disease state (Brosseau et al. 2003). midwives and patients report satisfaction with TENS ef- The beneficial effects of AL-TENS were achieved using fects. Interestingly, one RCT found significantly more particularly low dosage regimens of one 15 min ses- women and midwives favoured active rather than sham Transcutaneous Electrical Nerve Stimulation Outcomes 2513

Transcutaneous Electrical Nerve Stimulation Outcomes, Table 2 Physical Medicine, TENS outcomes Ref. Patients Results Reviewers’ Conclusion

Reeve et al. (1996) Acute pain (dysmenorrhoea, TENS >control in 7 / 14 RCTs Evidence inconclusive dental, cervical, orofacial)

Reeve et al. (1996) Postoperative pain TENS >control in 12 / 20 RCTs Evidence inconclusive

Carroll et al. (1996) Postoperative pain TENS >control in 2 / 17 RCTs Evidence of no effect

Bjordal et al. (2003) Postoperative pain 1350 patients (21 RCTs) Evidence of effect –analgesic sparing TENS >sham for reducing analgesic consumption (WMD = 35.5%)

Reeve et al. (1996) Labour Pain TENS >control in 3 / 9 RCTs Evidence inconclusive

Carroll et al. (1997) Labour Pain TENS >control in 3 / 10 RCTs Evidence of no effect

TENS when recorded under double-blind conditions at is absent from the majority of published RCT reports. theendofchildbirth(Harrisonetal.1986).Thissuggests In future, RCTs on TENS must take these factors into that the point in time that pain relief is recorded may in- account because they have been shown to alter TENS fluence the parturient’s report of TENS outcome in the outcomes. clinical trial situation. The low methodological quality of RCTs has created Systematic reviews on TENS and postoperative pain are uncertainty in the clinical research evidence for TENS. inconclusive or conflicting. TENS has been reported to TENS is a technique based intervention, so outcome is be no better than no treatment or sham TENS in 12 / 20 dictated by the appropriateness of TENS technique. The RCTs (Reeve et al. 1996) and in 15 / 17 RCTs (Carroll potential number of TENS protocols is vast, as users et al. 1996). However, pain relief scores were compro- can alter the characteristics of the electrical currents misedinsomeoftheincludedRCTsbecausepatientshad (i.e. the output characteristics), the application proce- free access to analgesic drugs, so they could titrate anal- dure (i.e. electrode type and location) and the dosing gesic consumption to achieve similar levels of pain re- regimen. Attempts to improve clinical effectiveness lief in sham and activeTENSgroups.Otherconfounding by searching for optimal TENS settings have largely factors include the difficulty of dichotomising multiple been unsuccessful. Nevertheless, an increasing number outcome measures, heterogeneous baseline pain mea- of non-standard TENS-like devices have appeared on sures and sample sizes with insufficient statistical power the market (e.g. interferential therapy (IFT), microcur- to detect potential differences between groups. A meta- rent electrical therapy (MET), transcranial electrical analysis of 1350 patients (21 RCTs) accounted for some stimulation and transcutaneous spinal electroanalgesia of these issues and found that TENS reduced analgesic (TSE)). Manufacturers overstate the potential effects consumption when compared to sham TENS (Bjordal et of these TENS-like devices and often similar levels al.2003).Asubgroupanalysisof964patients(11RCTs) of pain relief can be achieved using a standard TENS T that used optimal TENS dosage (i.e. a strong, subnox- device (Johnson 2003). ious electrical stimulation) found a significant improve- Health care professionals should not dismiss the use of ment in outcome suggesting that adequate TENS tech- TENS for any condition until the issues in clinical trial nique is necessary in order to achieve an effect. design and review methodology have been resolved. Often the appropriateness of TENS technique is not accounted for in methodological quality rating scales and / or inclusion criteria used in systematic reviews and References meta-analyses. Under-dosing of TENS has occurred in 1. Bjordal JM, Johnson MI, Ljunggreen AE (2003) Transcutaneous many trials using short duration, single or infrequent electrical nerve stimulation (TENS) can reduce postoperative TENS interventions. TENS effects are maximal when analgesic consumption. A meta-analysis with assessment of op- timal treatment parameters for postoperative pain. Eur J Pain the device is switched on and in practice users of con- 7:181–188 ventional TENS keep the device switched on whenever 2. Brosseau L, Milne S, Robinson V et al. (2002) Efficacy of the they need pain relief. However, many RCTs record transcutaneous electrical nerve stimulation for the treatment of pain outcome before and after TENS rather than during chronic low back pain: a meta-analysis. Spine 27:596–603 3. Brosseau L, YongeKA, Robinson V et al. (2003) Transcutaneous stimulation. Conventional TENS and AL-TENS are ill electrical nerve stimulation (TENS) for the treatment of rheuma- defined in published reports and are often categorised toid arthritis in the hand (Cochrane Review). In: The Cochrane accordingtotheelectricalcharacteristicsofTENSrather Library, Issue 3. Update Software, Oxford than the users’ intention to stimulate particular types of 4. Carroll D, Tramer M, McQuay H et al. (1996) Randomization is important in studies with pain outcomes: systematic review of nerve fibre and whether or not this was achieved during transcutaneous electrical nerve stimulation in acute postoperative the trial. Analysis of adequate stimulation technique pain. Br J Anaesth 77:798–803 2514 Transcutaneous Electrical Stimulation

5. Carroll D, Moore A, Tramer M et al. (1997) Transcutaneous of the stimulus (e.g. pressure or cold) into an electrical electrical nerve stimulation does not relieve in labour pain: up- signal. dated systematic review. Contemporary Reviews in Obstetrics  and Gynecology September 1997:195–205 Somatic Pain  6. Carroll D, Moore RA, McQuay HJ et al. (2003) Transcutaneous Species Differences in Skin Nociception electrical nerve stimulation (TENS) for chronic pain. In: The  Visceral Nociception and Pain Cochrane Library, Issue 3. Update Software, Oxford 7. Flowerdew M, Gadsby G (1997) A review of the treatment of chronic low back pain with acupuncture-like transcutaneous elec- trical nerve stimulation and transcutaneous electrical nerve stim- ulation. Complem Ther Med 5:193–201 Transduction Channel 8. Hansson P, Lundeberg T (1999) Transcutaneous electrical nerve stimulation, vibration and acupuncture as pain-relieving mea- sures. In: PD Wall, R Melzack (eds) Textbook of Pain. Churchill Definition Livingstone, Edinburgh, pp 1341–1351 9. Harrison R, Woods T, Shore M et al. (1986) Pain relief in labour Ionic channel gated (i.e. open or closed) by a physical using transcutaneous electrical nerve stimulation (TENS). A or chemical stimulus applied to the membrane of a pe- TENS / TENS placebo controlled study in two parity groups. ripheral sensory cell. Br J Obstet Gynaecol 93:739–746  10. Johnson M (2003) Transcutaneous Electrical Nerve Stimulation Nociceptor Generator Potential (TENS) and TENS-like devices. Do they provide pain relief? Pain Rev 8:121–128 11. McQuay H, Moore A (1998) TENS in chronic pain. In: McQuay H, Moore A (eds) An evidence-based resource for pain relief. Oxford University Press, Oxford, pp 207–211 Transduction Sites 12. Osiri M, Welch V, Brosseau L et al. (2003) Transcutaneous elec- trical nerve stimulation for knee osteoarthritis. In: The Cochrane Definition Library, Issue 3. Update Software, Oxford 13. Price CI, Pandyan AD (2001) Electrical stimulation for prevent- Membrane patches of sensory receptor terminals where ing and treating post-stroke shoulder pain: a systematic Cochrane review. Clin Rehab 15:5–19 sensory transduction takes place.  14. Proctor ML, Smith CA, Farquhar CM et al. (2003) Transcuta- Nociceptor Generator Potential neous electrical nerve stimulation and acupuncture for primary dysmenorrhoea. (Cochrane Review). The Cochrane Library, Is- sue 3. Update Software, Oxford 15. Reeve J, Menon D, Corabian P (1996) Transcutaneous electri- cal nerve stimulation (TENS): a technology assessment. Int J Transfected Cells Technol Assess Health Care 12:299–324 Definition Transfection refers to the introduction of exogenous Transcutaneous Electrical Stimulation genetic material encoding a gene of interest into cells. Transfected cells are used as model systems to study  Transcutaneous Electrical Nerve Stimulation Out- functional and structural properties of the transfected comes protein.  TranscutaneousElectricalNerveStimulation(TENS)  Purine Receptor Targets in the Treatment of Neuro- in Treatment of Muscle Pain pathic Pain

Transdermal Transfer and Generalization

Definition Definition The route of analgesic action is through transdermal ap- Transfer refers to the maintenance of learned behavior plication for systemic effect. change in the patient’s environment outside the treat-  Analgesic Guidelines for Infants and Children ment context; generalization refers to the extension of learned behaviors to similar problems.  Operant Treatment of Chronic Pain Transduction

Definition Transforaminal Injection of Steroids Transduction is the conversion of one form of signal to another.Forexample,insensoryendings,theconversion  Epidural Steroid Injections Transduction and Encoding of Noxious Stimuli 2515

of specialized proteins called receptors. Activation of Transduction and Encoding of Noxious these receptors by the different stimuli leads to a con- Stimuli formational change in the protein, forming pores in the membrane that allow the flow of ions (ion channels). CARLOS BELMONTE,FÉLIX VIANA Instituto de Neurociencias de Alicante, Universidad Stimulating Energy Miguel Hernández-CSIC, San Juan de Alicante, Spain Nociceptors were defined by Charles Sherrington as [email protected] sensory receptors activated by stimuli that potentially lead to tissue injury (noxious stimuli). Nociceptors, as in the case of other sensory receptors, are directly ac- Sensory Transduction tivated by a limited number of the various forms of en- Sensory transduction is the process by which external ergy that are continuously impinging upon the exter- physical changes are transformed into internal bio- nal surface and internal organs of the body and only chemical and/or electrical signals that are propagated within a narrow range of intensities (noxious stimuli). and processed through different levels of the central Effective stimuli include mechanical forces as well as nervous system to elicit a sensation. Despite the spe- temperature and a relatively large number of chemi- cialized design of sensory receptors for the different cal substances. The largest part of the electromagnetic sensory modalities, the cellular and molecular mech- spectrum goes undetected by nociceptors. Only when anisms involved in sensory transduction have certain the action of these otherwise unnoticed forces leads to common basic principles that can be outlined in a uni- cell damage may indirect stimulation of nociceptors fied scheme (Fig. 1) (Block 1992; Belmonte 1996). follow, due to release of chemical mediators by injured This process involves sequential detection, amplifica- cellslocated nearby. Thisisthe case, for instance, in ul- tion and filtering of the incoming signal. In nociceptor traviolet light or nuclear radiation exposure. What dis- neurons, as in other types of receptor neurons, the tinguishes nociceptors from low threshold sensory re- transformation of physical and chemical stimuli into ceptorsisnotthephysicalnatureoftheadequatestimuli electrical signals normally takes place at the periph- but the required threshold intensity for their activation eral nerve terminals, where the transduction machin- (Belmonte 1996). ery is located. This machinery is formed by a variety Perireceptor Elements Nociceptorsarenaked(orfree)nerveterminalsembed- dedinanintercellularmatrixthatcontainscollagenfib- rils and proteoglycansand devoid of specialized struc- tures (perireceptor elements) that in other receptors act as filters for the transmission of forces to the transduc- tion sites. Receptive areas in the nociceptor membrane appear to be discontinuous patches of bare axolemma, T covered only by the basal lamina of the nerve fiber and thus exposed to the direct action of stimuli. However, macromoleculespresentin the intercellularmatrix sur- rounding nociceptive nerve endings may play a role in the filtering of noxious stimuli reaching the receptive membrane. Transduction Molecules The diversity of forces that selectively activate noci- ceptor endings suggests that nociceptive neurons are equipped with separate transduction mechanisms for each of the stimulating energies. Nevertheless, some of the transducer molecules are multimodal and can be activated by more than one class of stimulus. The detection of stimuli by nociceptor neurons is based on membrane signaling molecules that con- vert the stimulus energy into an allosteric molecular Transduction and Encoding of Noxious Stimuli, Figure 1 Schematic diagram for sensory transduction steps. Adapted from Belmonte (1996) change, leading ultimately to the gating of membrane and Block (1992). ion channels and depolarization of the nerve terminal. 2516 Transduction and Encoding of Noxious Stimuli

Transduction and Encoding of Noxious Stimuli, Figure 2 Summary of transduction channels, modulatory molecules and voltage gated channels involved in noxious stimulus transduction and modulation and encoding of propagated nerve impulses by the various classes of nociceptors.

In nociceptors, most transduction molecules are ion mosensation, touch, hearing, thermal sensations and channelsdirectlygatedbythestimulus. Severalclasses pain (Clapham 2003). Members of the TRPC, TRPV of ion channelshave beenassociatedwiththe transduc- and TRPM families and TRPA1 (the single member tion of the various forms of energy and the production of the TRPA subfamily) are expressed in mammalian of generator potentials at nociceptor nerve terminals primary sensory neurons and participate in the trans- (Fig.2).Thelistofchannelslocatedatnociceptornerve duction of heat, cold, chemical stimuli and mechanical terminals continues to grow and their functional role forces. is under intense scrutiny. In addition, stimuli can in- The degenerin/epithelium sodium channel superfam- fluence other ion channels in the terminal and receptor ily (DEG/ENaC) includes five major subfamilies of molecules that are part of G protein signaling cascades channels (Kellenberger and Schild 2002). Mutations thatwillexertamodulatoryroleinthegenesisandprop- in some of the members, named degenerins, make agation of impulse discharges. constitutively active channels that lead to neurode- generation. DEG/ENaC channels are gated by gen- Transduction Channels Directly Gated by the Stimulus tle mechanical forces and mediate touch in nematodes The  TRP superfamily of cation channels is com- and flies. In vertebrates, the homologs of degener- posed of six subfamilies (TRPC, TRPV,TRPM, TRPP, ins include various subunits of Na+ selective,  acid- TRPML and TRPA). Many TRPs have emerged as im- sensing ion channels that are blocked by amiloride portant cellular sensors in a variety of sensory modali- and were called ASICs (Waldmann and Lazdunski ties including taste, olfaction, phototransduction, os- 1998). These subunits are encoded by 4 separate Transduction and Encoding of Noxious Stimuli 2517 genes and are processed in different splice variants. tissues. Recently, ionotropic receptors for excitatory Some subunits, such as ASIC1b and ASIC3, are ex- amino acids have been reported in nociceptive termi- pressed almost exclusively in the peripheral nervous nals, associated with their excitation during injury. system. Others, like ASIC2a, are expressed in special- ized mechanosensory structures. These channels have Remote Sensors and Modulators of the Stimulus twotransmembranedomainsandarethoughttoensem- Activation of metabotropic membrane receptor pro- ble into homomeric and heteromeric combinations of teins by endogenoussubstances released locally in the 4 subunits (i.e. tetramers). They are gated by protons environment of nociceptive nerve endings plays an im- and give rise to transient inward currents with fast acti- portant role in modulating their activity and respon- vating and variable desensitizing kinetics. In addition siveness following injury. These substances include to activation by low pH, some of these channels are peptides, kinins, purinesand excitatoryamino acids. In activated by mechanical forces and temperature and thiscase,theeffectsonnociceptormembraneexcitabil- could play important roles in nociception (Waldmann ity are not exerted directly on an ion channel. Rather, and Lazdunski 1998). the presence of an agonist substance causes the activa- The  two-pore domain superfamily of K+ channels tion of second messenger cascadesthatwillfinally lead (K2p) is a class of voltage insensitive, K+ selective to the opening or closure of ion channels. The effects channels that are open at rest. From this property they can be immediate or be the consequence of long-term are also known as background or leak K+ channels. changes in gene expression that include variations in They control neuronal excitability by changing the the number of ion channels and then sustained modifi- resting membrane potential and membrane resistance cations of neuronal excitability.Receptors of this type (Talley et al. 2003). Activity of these channels is reg- includethesuperfamilyofG-proteincoupledreceptors ulated by a variety of signaling molecules, including (GPCR); a large number of G-protein coupled recep- protons, O2 tension polyunsaturated fatty acids and tors have been shown to be present in sensory nerve phospholipids (Patel et al. 2001). They are also modu- endings and up- and down-modulate their excitability lated by physical variables such as mechanical stretch following application of the specific ligand. Very of- and temperature, making them candidates for sensory ten sensitization is specific to a certain type of stimu- transduction channels. Various K2p subunits have been lus(mechanicalversusthermal). The list ofpro-algesic identified in primary sensory neurons. However, very substances includes acetylcholine, bradykinin (BK), little information is available regarding the expression noradrenaline, histamine, serotonin, PGE2 and nerve pattern in specific subpopulations of somatosensory growth factor (NGF).Among the GPCRs capable of afferents. K2p2.1 (TREK-1), K2p10.1 (TREK-2) and acutely sensitizing nociceptors, we count B1 and B2 K2p4.1 (TRAAK) may play a role in mechanosensory BK receptors and alpha-1, alpha-2 and beta-2 adren- and thermal transduction (Patel et al. 2001; Kang et al. ergic receptors. Histamine H1 receptors also sensi- 2005). Some of these channels, such as members of the tize nociceptors. The sensitization of nociceptors pro- TASK subfamily, are closed by extracellular acidic so- duced by bradykinin through the activation of B2 and lutions leading to depolarization and could be involved B1 receptors involves the phospholipase C and pro- T in pH sensing by nociceptors (Talley et al. 2003). tein kinase Csignaling pathwaysthat lead ultimately to Several types of Ligand-gated ion channels are also the modulation of the TRPV1 (capsaicin) ion channel present in nociceptor neurons and may play a role (Chuang et al. 2001; Vellani et al. 2001). in transduction of stimuli. These channels open in In contrast, M2 muscarinic receptors participate in the response to a variety of chemical substances, some depression of nociceptive responsiveness to heat and of which are released locally following tissue injury. mechanical stimulation produced by the acetylcholine A prominent example is offered by the family of liberated during injury by skin keratinocytes and other  ionotropic purinergic receptors (P2X). These are local cells. Activation of somatostatin sst2 receptors, ATP gated, cation selective ion channels. Of the seven present in about 10% of cutaneous afferent terminals, P2X channels identified so far, all except P2X7 are ex- also has antinociceptive effects. Intradermal injection pressed in sensory neurons (Burnstock 2000). Only of metabotropic glutamate receptor type 5 antagonists the P2X3 subunit is selectively expressed in nocicep- produces full reversal of thermal hyperalgesia in an- tors (Chen et al. 1995). Also, some members of the imal models of neuropathic pain. Opiates also exert Cys-loop family of transmitter-gated ion channels are a peripheral antinociceptive activity and these uncon- present in nociceptive terminals. These include the ventional effects of opioids appear to be mediated by cation permeable nicotinic ACh receptors and the opening of K+-ATP channels following activation of 5-HT3 serotonin receptors, which are non-selective the arginine/NO/cGMP/ pathway by protein kinase G. cation channels, gated respectively by acetylcholine Tyrosine kinase receptors, another superfamily of and serotonin, substances that are released in inflamed membrane receptor proteins, also participate in the 2518 Transduction and Encoding of Noxious Stimuli

modulation of nociceptor excitation. This group in-  ‘silent’ nociceptor nerve fibers but they are obtained cludes trkA receptors that are activated by nerve following local tissue inflammation. Ion channels di- growth factor (NGF) released by injury in the en- rectly gated by mechanical stimuli were first recog- vironment of nociceptive terminals. The effect of nized in the 1980s but the identification of the molecu- NGF appears to be mediated in part by the same lar entities involved in the transduction of mechanical mechanism that is activated by BK, namely PLC forces remained elusive until recently. stimulation with subsequent hydrolysis of membrane Mechanical distortion, like stretch or pressure, pro- phosphatidylinositol-4,5-bisphosphate (PIP2) yield- duces the opening of mechanically sensitive channels ing inositol 1,4,5-trisphosphate (IP3) and diacylglyc- (mechanosensitive channels, MSCs). MSCs are a het- erol.OnefinaltargetofthiscascadeistheTRPV1chan- erogeneous population of channels with differences in nel, which is modulated both by PKC dependent and sensitivity, type of response, pharmacology and bio- independent mechanisms (Vellani et al. 2001; Chuang physical properties like ionic selectivity conductance et al. 2001). and adaptation. They are present in a great variety of  Proteinase-activated receptors (PARs) are also cell types and, in addition to stimulus detection, par- members of the superfamily of G-protein coupled re- ticipate in a variety of other cell functions, such as ceptors.Theyinitiateintracellularsignalingbythepro- volume regulation, cell movement, cell division, os- teolytic activity of extracellular serine proteases that mosensation and contraction. The effect of mechan- cleave the N-terminusof the receptor.PAR-1 andPAR- ical force on a channel can be direct, leading to gat- 2 are expressed in many peptidergic sensory neurons ing by tension exerted directly on the channel proteins and their activation induces neurogenic inflammation or indirect, involving second messengers controlled and mediates peripheral sensitization of nociceptors by mechanosensitive enzymes. However, the precise (Vergnolle et al. 2003). mechanism coupling the supply of energy provided by Membrane lipids are emerging as a new class of ion the mechanical stimulus to the gating of the channels channelmodulators,withimportantimplicationsinno- is still unresolved in nociceptors. ciceptor activation. A growing list of ion channels are The molecular identity of ion channels involved in the modulated directly by interactions with phosphatidyli- transductionoflowintensitymechanicalforcesbyspe- nositol 4,5-bisphosphate (PIP2) (Suh and Hille 2005). cific mechanosensory cells has been partly elucidated As already mentioned, a number of agonists exert their in ciliated mechanosensory cells of invertebrates and actions by their ability to activate the phospholipase C in the hair cells of the auditory, vestibular and lateral (PLC) signaling pathway, which stimulates phospho- line organs of vertebrates (reviewed by Corey 2003). inositide hydrolysis. The end result is a reduction in With the application of genetic screens, Deg/ENaC theconcentrationsofplasmamembranephosphoinosi- channels and TRP channels have been identified as tides to produce IP3. In the case of TRPV1, a reduc- essential for mechanosensation in different types of tioninmembranePIP2levels, as occurs when PLC is mechanosensorsinfliesandworms.Inmostcaseshow- stimulated by NGF or BK, leads to channel activation ever, it remains uncertain whether they are the trans- (Chuang et al. 2001). The opposite appears to occur for duction channels themselves and what are the specific TRPM8 channels, inhibited by low PIP2 levels. mechanisms of activation. The fact that mechanosen- sation requires the concerted function of several pro- Transduction Mechanisms for the Different Stimuli teins acting in an ensemble ( transduction apparatus) Ion channels and receptor proteins of the different su- make these studies especially difficult. perfamilies exhibit a variable sensitivity to mechanical In the nematode C. elegans, gentle touch mechanosen- forces, chemical substances, heat or cold. The charac- sation depends on members of the DEG/ENaC fam- teristic expression patterns of these proteins in the var- ily. In particular, mutations in the channel subunits ious subtypes of nociceptor neurons confer on them MEC-4 and MEC-10 led to loss of responses to touch their specific transduction capabilities for the different and abolished mechanotransduction currents. OSM- forms of stimulating energy. 9 and OCR-2, two related TRPV channels are also required for touch sensitivity in the nose region in Mechanotransduction C. elegans. In flies, TRPN1 (previously known as Propagated impulse responses to mechanical forces NompC) is essential for mechanotransduction in sen- are prominent in the peripheral endings of noci- sory bristles. This channel is also at the core of ceptor neurons exclusively activated by mechanical mechanotransduction in zebra fish hair cells. Sur- stimuli ( mechano-nociceptors); they also appear in prisingly, no TRPN-like genes could be found in  polymodal nociceptor neurons that are additionally higher vertebrates. Also in flies, a TRPV-like chan- excited by chemical and thermal stimuli. Mechani- nel protein, NAN, is expressed selectively in chordo- cally evoked nerve impulse discharges are absent in tonal neurons and is essential for hearing. No ortho- Transduction and Encoding of Noxious Stimuli 2519 loguesof nanchung havebeen identifiedinvertebrates, in somas and peripheral terminals of primary sen- suggesting that, in this case, hearing is mediated by sory neurons (reviewed by Kellenberger and Schild different transducers. Genetic screens in Drosophila 2002). Nonetheless, assigning a functional role to spe- larvae for mutations that alter responses to noxious cific subunits is complicated by the fact that, in most mechanical and thermal stimuli identified Painless,a cases, functional channels in vivo are heteromulti- TRPAchannel(TraceyJretal.2003).Recently,TRPA1 meric. Somewhat predictably, knockout of individual channels have been located on apical hair bundles (i.e. ASIC subunits in mice only leads to modest deficits in the mechanotransduction site) of vertebrate hair cells. touch sensitivity. The existence of numerous touch re- Furthermore, inhibition of TRPA1 expression inhibits ceptors with overlapping mechanical sensitivities and transduction currents generated by the movement of intermixed receptive fields limits the possibility of the cilia (Corey et al. 2004). marked functional deficits in the case of single gene In contrast to this knowledge, the nature of the chan- disruptions. In addition, properties of human subunits nels directly involved in the transduction of mechan- are not identical to those displayed by homologs in ical stimuli by mammalian somatosensory endings is other species. So far, there is no definitive evidence largely ignored. Moreover, the differences in threshold for a major role of a particular ASIC subunit in so- and adaptation characteristics found between low- and matosensory mechanotransduction.Early studies sug- high-threshold mechanoreceptor neurons are still un- gested that loss of ASIC2a reduced the sensitivity of explained at the cellular level. These differences may low threshold rapidly adapting Aβ mechanoreceptors simply lie in the density of mechanosensory channels to touch. Deletion of ASIC3, also know as DRASIC, in the transducing areas, be due to the presence of dif- increased the sensitivity of mechanoreceptors detect- ferent types of mechanosensory transduction channels ing light touch, but reduced the sensitivity of Aδ noci- or to other factors like variations in the arrangement ceptors responding to noxious pinch. However, other or composition of the mechanotransduction appara- studies indicate that lack of ASIC1, ASIC2 or ASIC3 tus, cytoskeleton organization and/or second messen- does not impair cutaneous or visceral mechanosensa- ger pathways. tion nor does it reduce mechanogated currents in the Several channels with apparent mechanosensitivity soma of DRG neurons (Roza et al. 2004). have been identified in primary sensory neurons of Theroleofthelipidsensitive,mechano-gatedK+ chan- mammals but evidence for their direct mechanical nelsTREK-1,TREK-2andTRAAKoftheK2Pchannel activation is slim in all cases. Candidate transducer family in nociceptor mechanotransduction is still open molecules for mechanotransduction include TRP to discussion (Patel et al. 2001). channels and members of the acid-sensing ion channel P2 purinergic receptors also seem to participate in- (ASIC) family. Modulatory roles have been assigned directly in mechanotransduction, possibly modu- to other channels like K2P channels and purinergic lating the opening probability of other classes of receptors. mechanosensory channels. Expression of P2Y1 recep- Within the TRP superfamily of ion channels, TRPC1 tors in oocytes determines the development of ionic andTRPV4appeartobesensitivetomembranestretch. responses to the application of light mechanical stim- T TRPC1 is highly expressed in frog oocyte membranes uli. These stimuli appear to release intracellular ATP andopensinresponsetotensionexertedwithinthelipid that in turn activates P2Y1 receptors (Nakamura and bilayer (Maroto et al. 2005). TRPC1 is also found in Strittmatter1996).Similarly,releaseofATPfromdam- visceral sensory neurons, including fine nerve termi- aged cells following mechanical injury may stimulate nals within the carotid body. TRPV4 opens in response P2X receptors present in small unmyelinated fibers toosmoticcellswellingwhenexpressedinmammalian and may be involved in mechanical sensitivity of no- cultured cells. TRPV4 isa multifunctional channel that ciceptors (Cook and McCleskey 2002). is also activated by warm temperatures and lipoxy- Finally, mechanical stretching modifies the activ- genase metabolites (Patapoutian et al. 2003). Percep- ity of voltage dependent Ca2+ channels but not of tion of noxious pressure is reduced in trpv4-/- mice, Na+ and K+ channels or K+ leakage channels. The while gentle touch detection is unimpaired. However, mechanosensitivityofCa2+ channelsmaycontributeto TRPV4 doesn’t appear to be directly mechanosensi- modulating the neuron response to mechanical stimuli tive; rather, its activation appears to depend on a sec- through changes in intracellular Ca2+. ond messenger cascade. Finally, TRPA1 channels are Extracellular matrix attachments have been proposed present in a large proportion of mammalian DRG neu- as the general mechanism involved in transmitting rons and may be activated by mechanical forces, as oc- external mechanical forces to the neuron surface curs in hair cells. and subsequently to MSCs. In turn, MSCs are teth- Among channels of the DEG/ENaCs superfamily, ered to the internal cytoskeleton. Relative displace- ASIC1, ASIC2 and ASIC3 subunits are expressed ment of these structures would transmit tension to 2520 Transduction and Encoding of Noxious Stimuli

minals without producing a propagated discharge, by changing their responsiveness to further stimuli. Endogenous compounds that influence the excitabil- ity of nociceptors include protons, low oxygen (i.e. hypoxia), arachidonic acid and metabolites (e.g. prostaglandins), kinins, amines like serotonin and his- tamine, cytokines (e.g. tumor necrosis factor α,IL-1β and IL-8), acetylcholine, amino acids, NO, opioids, ATP,adenosine, endocannabioids and other neuropep- tides (e.g. endothelin-1). Many of these substances are released as part of the injury/inflammatory response caused by noxious stimuli and will trigger or modu- late the transduction process. In addition, a number of growth factors influence nociceptor excitability either directly or by regulating gene transcription, result- ing in altered ion channel expression. These types of substances include nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), glial cell derived neurotrophic factor (GDNF) and related factors. Considering thediversephysicochemicalpropertiesof exogenous sensory irritants, it is doubtful that all of them act through a specific receptor molecule. It is more likely that some of the compounds that stimulate nociceptive nerve endings partition in the membrane according to their liposolubility and alter membrane Transduction and Encoding of Noxious Stimuli, Figure 3 Hypo- and cellular properties, including surface charge, gat- thetical arrangement for the different elements of the mechanotransduc- ing of ion channels and metabolic state of the cell. The tion apparatus. External mechanical forces are transmitted by extracellu- net result of these actions is a depolarization of nerve lar matrix molecules and cytoskeleton proteins to mechanotransduction terminals and a discharge of nerve impulses, whose fir- channels, causing an ion current flow through the open channel. ingfrequencymaybeproportionaltotheconcentration of the irritant substance within certain limits. In con- the gate of the mechanosensory channel. Altogether trast, many other exogenous and endogenous chemi- theyformafunctionalunitycalledthemechanosensory cals and protons directly or indirectly gate members of apparatus(Fig.3).Ithasbeensuggestedthattransmem- the various superfamilies of ion channels, leading to braneintegrinsactasamolecularlinkerbetweentheex- changes in membrane potential (Julius and Basbaum tracellular mechanical signal and the cytoskeleton, be- 2001). cause they bind actin associated proteins and therefore TRPV1 (originally named VR1), a member of the physically link the extracellular matrix with the micro- TRPV subfamily, is a receptor for capsaicin, the pun- filaments. Other cellular elements, such as certain en- gent compound found in hot peppers, and appears to zymes, can be directly sensitive to stress and act addi- play a central role in the sensitization of nociceptors tionallyasmechanotransducers.However,thelowsen- to many endogenous substances (Caterina et al. 1997). sitivity and slow time course of the evoked responses This channel is also activated by protons and nox- make their direct responsibility in sensory mechan- ious heat (over 42˚C). TRPV1 is a non-selective cation otransduction dubious. channel with a very high permeability to Ca2+.Sen- Chemotransduction sory neurons expressing native TRPV1 receptors and A great variety of molecules, either exogenous or en- oocytes or mammalian cells transfected with TRPV1 dogenous, act on nociceptive terminals, producing a exhibit robust membrane currents in response to cap- change in membrane potential and eventually a dis- saicinthataredesensitizedbyrepeatedexposurestothe charge of nerve impulses (Belmonte 1996; Julius and agonistandblockedbythecompetitivevanilloidrecep- Basbaum 2001). Sensitivity to chemicals is present tor antagonist capsazepine and by the non-competitive to a variable degree in all subpopulations of nocicep- antagonists ruthenium red and peptoids. The channel tors. In some cases (polymodal nociceptors, silent no- is also activated by various endogenous lipids, such ciceptors) chemicalmediatorsactivate thenerve termi- as anandamide, the ligand for cannabinoid receptor nals directly. In others (mechano-nociceptors), chem- 1. Moreover, the endogenous inflammatory mediator ical mediators may alter the excitability of nerve ter- bradykinin (BK) that is known to sensitize polymodal Transduction and Encoding of Noxious Stimuli 2521 nociceptor endings through activation of the G- brane patches of TRPV1-transfected cells also in- protein-coupled receptor BK2 also enhances capsaicin creaseswhentheexternalpHisreduced. Theacidsens- currents. A similar effect is produced by nerve growth ing ion channels (ASIC), members of the DEG/ENaC factor (NGF), which also sensitizes polymodal nerve superfamily, are also activated by extracellular protons endings to noxious stimuli by activation of the tyrosine and are over-expressedduring inflammation. The con- kinase receptor TrkA. In addition, GDNF up-regulates tribution of different DEG/ENaC channel subunits to B1 receptor expression in small non-peptidergic noci- pHsensitivecurrentsin DRGneuronshasbeen investi- ceptive neurons. Furthermore, activation of B1 recep- gated with targeted disruption of the various subunits. tor causes a marked increase in the amplitude of the Deletion of any one subunit did not abolish proton- heat-activated current in these neurons. BK2 and TrkA gated currents, suggesting that two or more ASIC sub- receptors act through the stimulation of phospholipase units coassemble as heteromultimers. As mentioned C (PLC), which enhances both basal TRPV1 activity above, ASIC3 is present in presumed primary nocicep- and capsaicin-evoked responses. PLC catalyzes the tive neurons of the mouse and possibly participates in hydrolysis of membrane PIP2 to form IP3 and diacyl- thedetectionofstronglocalpHreductionsaccompany- glycerol. PIP2 inhibits TRPV1 channels directly and ingischemiaorinflammation.Thischannelisprobably its hydrolysis results in TRPV1 potentiation (Chuang involved in the sensation of cardiac pain (Sutherland et et al. 2001). In contrast, potentiation of TRPV1 by B2 al. 2001). The ASIC3 knockout mouse exhibits a low- and P2Y2 receptors appears to be mediated by protein ered sensitivity to intramuscular injection of acid. Fur- kinase C (PKC) activation. thermore, DRG neurons respond less to low pH solu- It has been claimed that ATP released by injured tion. Psychophysical and pharmacological data in hu- cells excites nearby nociceptive terminals. Impulse re- mans suggest that ASIC channels have a more impor- sponses to ATP have been evoked in the soma and neu- tant role than TRPV1 channelsin the sensation of mod- ritesof tooth pulp cultured nociceptiveneuronslabeled erate cutaneous acid induced pain. retrogradely (Cook et al., 1997). This effect is medi- Among the K2P channels, TASK subunits (TASK-1, atedbyP2X3ionotropicchannels.Also,inmammalian TASK-2, TASK-3) represent background outward rec- cells expressing cloned TRPV1 channels and in DRG tifiers that are constitutively active at all voltages and neurons, ATP enhances the responses to capsaicin, to are inhibited by extracellular acidic pHvalues. Closure heat and to protons (Moriyama et al. 2003). This effect of these channels depolarizes the membrane potential. seemstobesecondarytoactivationofthemetabotropic TASK channels have been found in some sensory neu- purinergic receptor P2Y2, that activates phospholipase rons with nociceptive properties but their role in pH- C through a G–protein (Gq/11), leading to the produc- induced pain has not been firmly established yet. tion of IP3 and diacylglycerol. Among 2-pore domain K+ channels, TREK-1, TREK- Thermal Transduction 2 and TRAAK are gated by different biolipids like arachidonic acid and lysophosphatidic acid (Pateletal. Extremely low or high temperatures evoke distinct 2001). pain sensations that are mediated by activation of sub- T populations of sensory afferents. Heat activates poly- Acid Sensing modal nociceptor fibers, which respond to tempera- Intradermal injection of acidic solutions induces pain. tures greater than 41˚–42˚C. For the sensation of pain Furthermore, tissue acidosis is a common occurrence evoked by cold, it was suggested that a specific group following inflammation, ischemia and tissue injury. of cold-activated sensory fibers might exist. However, This acidosis, to pH values as low as 5, is known to there is also evidence favoring the view that the sen- activate and sensitize polymodal nerve terminals (Bel- sation of cold pain rather results from the concomitant monte et al. 1991). In fact, most acid sensing neurons activationbylowtemperaturesofnon-nociceptivecold havesmalldiameters,typicalfornociceptors.Theexci- thermoreceptors and a fraction of polymodal nocicep- tatory effects of protons could be mediated by a variety tors (Campero et al. 1996). The transduction mecha- of ion channels including TRPV1, ASICs and TASK nisms for heat and cold in primary sensory neurons ap- channels that are sensitive to pH changes. These find- pear to be different at the cellular and molecular levels ings are of great significance in explaining the pain and (Fig. 4). Several receptor molecules have been iden- primary hyperalgesia that appear during inflammation tified recently that seem to be involved in the detec- and ischemia. tion of temperature changesgreater thannormalvalues In TRPV1-transfected cells, protons evoke distinct in- (Patapoutian et al. 2003). In contrast, the cellular and ward currents and enhance the response to capsaicin molecular mechanisms involved in the detection of in- up to five times over control values (Caterina et al. nocuousversusnoxioustemperature decreasesare still 1997). Single channel activity in outside-out mem- incompletely understood. 2522 Transduction and Encoding of Noxious Stimuli

Transduction and Encoding of Noxious Stimuli, Figure 4 Diagram of ion channels hypothetically involved in transduction of innocuous and noxious temperatures by peripheral sensory receptor terminals. neurons the specific transduction mechanisms for Heat heat were closely associated with chemosensitivity to Temperature elevations influence ionic pumps and capsaicin. conductancesinallcelltypesincludingnociceptiveter- Cesare and McNaughton (Cesare and McNaughton minals. However, polymodal nociceptor nerve fibers, 1996) first described an inward current in a subpop- unlike thermal sensory fibers that detect innocuous ulation of small dorsal root ganglion neurons that was warming, begin to discharge nerve impulses when the activatedbynoxiousheat,sensitizedbybradykininand tissuetemperatureincreasesover40˚C.Moreover,they presumably mediated by a non-selective cation chan- become sensitized by repeated thermal stimulation in nel. Identification and cloning of the ‘capsaicin recep- the noxious range. Based on threshold, latency and tor’ TRPV1 (Caterina et al. 1997) proved that heat is a peak discharges to controlled heat pulses, two types of stimulus for this channel as well as for other channels impulse responses were identified in separate groups of the TRPV family. Heat induced currents in mem- of Aδ nociceptors. One had a high threshold (over brane patches of TRPV1 transfected cells showed the 53˚C), a slow build-up and latencies measured in sec- same outwardly rectifying current-voltagerelations as onds; the second type was characterized by a lower those evoked with capsaicin. Both were blocked by threshold (46˚C), latencies measured in milliseconds capsazepine and displayed analogous ionic selectivi- and rapid peak discharges. In turn, C nociceptors be- ties. However, in transgenic mice where the TRPV1 gin to respond at around 41˚C, giving a peak dis- gene was disrupted, sensitivity to capsaicin was lost, charge near the stimulus onset. Overall, these obser- while responses to noxious heat still persisted. Also, a vations suggest that various transduction mechanisms fraction of cultured primary sensory neurons respond may contribute to the final activation of nociceptors to heat but not to capsaicin. A candidate molecule for by heat. Changes in responsiveness of polymodal no- the additional sensitivity to noxious heat is another ciceptive terminals to heat often go in parallel with a vanilloid receptor-like channel named TRPV2 that is modified chemosensitivity. Thus, thermo- and chemo- 50% identical to TRPV1, responds to heat over 52˚C sensitivities were simultaneously altered by capsaicin and is insensitive to capsaicin, being inhibited by the and exhibited cross-sensitization (Belmonte et al. non-competitive antagonist ruthenium red (Caterina et 1991).Theseobservationssuggestedthatinpolymodal al. 1999). Transduction and Encoding of Noxious Stimuli 2523

Finally, sensitivity to rising temperatures has been ion channel of the TRP family, TRPM8 (originally shown in two more members of the TRPV family. named CMR1 because of its cold and menthol sensi- TRPV3 is structurally analogous to TRPV1 and is tivity, McKemy et al. 2002; Peier et al. 2002) that is expressed in the skin keratinocytes, the brain and found in about15%ofprimarysensory neurons. Inhet- other tissues. When transfected into mammalian cells, erologous expression systems, TRPM8 channels acti- this channel responds to temperature with a thresh- vateattemperaturesbelow25˚C,atemperaturenotably old around 33˚C but not to capsaicin or pH changes, lower than the activity threshold of cold thermorecep- showing an activation profile closely similar to that of tors (de la Pena et al. 2005). However, this mechanism TRPV1 (reviewed by Patapoutian et al. 2003). TRPV3 is possibly not sufficient to explain the firing charac- is also activated by camphor. Although no immunore- teristics of cold receptors and the differences in sen- activity to this channel can be found in the neurons sitivity to temperature of the various types of thermal of peripheral sensory ganglia, TRPV3 null mice have receptors. Cold also closes a background K+ current in strong deficits in responses to innocuous and noxious the soma of cultured cold sensitive neurons (Viana et heat, indicating that it participates in thermosensation al. 2002; Reid 2005), producing a net inward current (Moqrichetal.2005).TRPV4,acationchannelthathas (Icold) that leads to depolarization and impulse firing. been implicated in hypo-osmolality sensing by neu- This effect is partly counteracted by the prominent in- rons of the anterior hypothalamus, is also tempera- wardly rectifying Ih current present in these cells that ture sensitive when expressed in oocytes and HEK 293 tends to depolarize the neuron at the basal membrane cells,withanactivationthresholdof25˚Candmaximal potential but decreases progressively with depolariza- responses around 40˚C (Guler etal. 2002). Thus, trans- tion as well as as a consequence of the direct action of duction of heat by primary sensory neurons appears to cold. Depolarization by cold occurs in other types of be mediated by several ion channel proteins that cover primary sensory neuron but they are less sensitive than different temperature ranges and may explain the dif- coldspecificneurons,becausetheyexpressaslowlyin- ferences in heat threshold among nociceptors. Forma- activating, transient, outward current named IKD that tion of heteromeric channel assemblies by the mem- reduces their excitability during cooling and prevents bers of the TRPV subfamily in nociceptive neurons is the impulse discharge. Low concentrations of 4-AP se- an additional possibility for explaining the presence of lectively block this current and render cold insensitive a range of receptors with a wide spectrum of responses neurons responsive to cold (Viana et al. 2002). to temperature. Noxious Cold Cold The reduction of cutaneous surface temperature below The identification of the cellular mechanisms involved 15˚C elicits a sensation of cold pain. The discovery of in the transduction of cold stimuli by low- and high- TRPA1, a TRP channel that is expressed in a fraction threshold cold thermal receptors has been quite elu- of primary sensory neurons, some of which also har- sive.Low-threshold(innocuous)coldsensoryfibersin- bor TRPV1 channels, and the fact that TRPA1 is acti- crease their firing frequency with changes of skin tem- vated by temperatures below 18˚C made it a good can- T perature as small as 0.01˚C (Gallar et al. 2003). On didate for the transduction of noxious cold (Story et al. the other hand, high-threshold cold fibers responding 2003). However, TRPA1 is also gated by a number of specifically to cutaneous cold below 27˚C have been pungent compounds like cinnamaldehyde, mustard oil reported (reviewed by Reid 2005). Finally, a fraction and allicin that, when applied to the skin, evoke a burn- ofpolymodalnociceptorafferentsdischargewhenthey ing rather than a cold sensation (Namer et al. 2005). are exposed to very low temperatures (Campero et al. These findings and the disputed activation of TRPA1 1996; Acosta et al. 2001). by low temperature leave the specific role of TRPA1 Theunifyinghypothesisoriginallyproposedtoexplain in the transduction of noxious cold temperatures un- the sensitivity of primary sensory neurons to low tem- settled. In neuropathic pain models, the time course of peratures was that the electrogenic Na+-K+ pump was cold hyperalgesia matches the expansion of a popu- highly temperature dependent, so that temperature de- lation of TRPA1 expressing neurons, but only in the creases cause a reduction in pump activity, leading to uninjured ganglion (Obata et al. 2005). Cultured pri- depolarization. The differential temperature sensibil- mary sensory neurons responding to cold have a wide ity of sodium and potassium ion channels would ad- range of temperature thresholds from 32˚C to 18˚C, ditionally contribute to a depolarized membrane po- butexhibithomogeneousmembranepropertiesandfir- tential during cooling. However, blockers of the Na+- ing characteristics and the great majority are sensi- K+ pump do not eliminate the sensitivity of cold sen- tive to the TRPM8 activator, menthol. About 50% of sory fibers to temperature decreases. More recently, them are also activated by capsaicin(Viana etal. 2002). it has been proposed that cold selectively activates an Therefore, the possibility that noxious cold is signaled 2524 Transduction and Encoding of Noxious Stimuli

by a fraction of cold sensitive neurons biophysically channels in nerve terminals and their opposite effects analogous to those responding to innocuous cold but on cell firing, the net change in excitability may not al- with different central connections cannot be excluded. ways correspond to that predicted by disturbances in In that respect, it is interesting that topical application a single class of voltage gated ion channel. of menthol, the specific agonist of TRPM8 channels, + canalsoinducesensationsofirritationandpain(Acosta Na Channels et al. 2001; Wasner et al. 2004). Nonetheless, there is Pharmacologically,  voltage-gated Na+ channels experimental evidence that noxious cooling also acti- have been broadly separated into two groups; one class vatesidentified polymodalnociceptor fibersinanimals is blocked by nanomolar concentrations of the natu- and humans. Thus, it is also possible that noxious cold ral marine toxin tetrodotoxin (tetrodotoxin-sensitive, sensations are evoked through the parallel excitation TTXs) while the other group of Na+ channels is resis- of polymodal nociceptor and innocuous cold receptor tant to tetrodotoxin ( tetrodotoxin resistant, TTXr). fibers by very low temperatures. The results of various molecular approaches indicate that nine of the ten alpha subtypes of sodium channels Generation and Encoding of Nerve Impulses are present in sensory neurons. Some of these chan- In nociceptors, the change in local membrane conduc- nels are found in virtually all sensory neurons, while tance caused by physical and chemical stimuli is ex- others, specially the TTXr subtypes, show a more re- pected to produce a generator potential (see genera- stricted expression pattern. The expression profile also tor current), whose magnitude and duration will reflect changes during development. the intensity, duration and time course of the stimu- Propagation of action potentials along all sensory ax- lus. These generator potentials associated with gating onsismediated by TTXschannels. In contrast, some of + of transduction channels in nociceptive terminals have the TTXr Na channels subtypes (Nav1.8 and Nav1.9) never been recorded, due to technical limitations im- are selectively found in small diameter, primarily noci- posed by the small size of nociceptive endings. The ceptive neurons (Akopian et al. 1996; McCleskey and generator potential will in turn propagate electroton- Gold 1999). Nav1.8 channels are particularly abun- ically and initiate, at the closest point of the axonal dant in polymodal nociceptive terminals, where they membrane endowed with regenerative properties, a can sustain propagated action potentials that may con- discharge of propagated nerve impulses, whose fre- tribute to local release of  neuropeptides (Brock et al. quency of discharge is also proportional to the ampli- 1998). tude of the stimulus. The various ion channels asso- Expression of Na+ channels is up- or down-regulated ciated with the stimulus transduction and the genera- following local inflammation and injury of peripheral tion of electrical activity in primary nociceptive neu- sensory axons (Lai et al. 2004). Functional properties rons appear to be distributed unevenly among the pe- are also affected by injury. These factors possibly con- ripheralterminalarborizations, theparentaxon andthe tribute to the changes in sensitivity and the ectopic ac- cellbody,thusconferringdifferentelectricalproperties tivity found in damaged sensory nerves that may give on the different portions of the neuron. rise to  neuropathic pain. The role of Na+ channels in hyperalgesia is further substantiated by the effective- Voltage-gated Channels and the Encoding Noxious Stimuli ness of use-dependent sodium channel blockers for the Primarysensoryneuronsalsoexpressionchannelsthat treatment of various types of chronic pain. It must be gate in response to changes in membrane potential and noted that abnormal activity in uninjured primary af- whose primary role in terms of stimulus detection is ferents may also be critical for the observed hypersen- not transduction but propagation and modulation of sitivity to sensory input in animal pain models (Lai et the impulse discharge. They belong to the superfamily al. 2004).  of voltage-gated channels that includes a large va- + riety of K+,Na+ and Ca2+ channels, Cl- channels and K Channels non-selective cation channels like the HCN channels Potassium channels form a diverse superfamily of ion (hyperpolarization activated cyclic nucleotide gated channels. On the basis of their structure and func- K+ channels) (Hille 2001). Nociceptors have charac- tional properties they can be separated into voltage teristic electrophysiological properties (Koerber and gated (Kv), calcium activated (KCa), inward recti- Mendell 1992) and many different voltage gated ion fier (Kir) and two-pore domain K2P channels. They channels contribute to their cellular excitability. are involved in a variety of neuronal functions in- Abnormal excitability of injured neurons has been cluding maintenance of membrane potential, action linked to alterations in the expression and functional potential repolarization and regulation of firing fre- characteristicsofmanytypesofvoltagegatedionchan- quencyandarecriticalregulatorsofneuronalexcitabil- nels (Cummins et al. 2000). Given the diversity of ion ity (Hille 2001). Because K+ ions have a negative equi- Transduction and Encoding of Noxious Stimuli 2525 librium potential across the plasma membrane, activa- tomembranedepolarization.Theyhavethespecialrole tion of these channels tends to dampen excitation. of translating electrical signals into chemical signals through their control of the flow of Ca2+ ions into the cytoplasm, thereby regulating a variety of Ca2+ de- Voltage Gated K+ Channels (Kv) pendent intracellular events (Hille 2001). Functional A large number of Kv channels are expressed in noci- and pharmacological studies followed by cloning and ceptors (McCleskey and Gold 1999). A variable com- genetic analysis have led to the identification of a bination of rapidly inactivating A-type (IA)andslowly large number of voltage gated Ca2+ channels. Sub- + or non-inactivating (I K)K currents are observed in populations of primary sensory neurons exhibit dif- the various types of nociceptor neurons. These func- ferences in their functional type of Ca2+ channels and tional currents can be further subdivided into sev- some subunits are selectively expressed in nociceptors eral types with distinct kinetic and pharmacological (Bell et al. 2004). The properties of voltage-gated Ca2+ components. Pharmacological, functional and genetic channels are modulated directly and indirectly by a + studiesconfirm thatK channelsplay a role in nocicep- number of endogenous mediators released during in- tor excitability. Furthermore,severalKvchannel genes jury, thereby changing the excitability and responsive- are down-regulated in sensory neurons following axo- ness of nociceptive neurons. The expression of voltage tomy or chronic constriction of peripheral nerves, sug- gated Ca2+ channel subunits is also altered in condi- gesting that, together with Nav channels, they partici- tions such as peripheral nerve injury, contributing to pate in the alteration of axonal excitability that accom- abnormal nerve activity and neuropathic pain. In ad- panies peripheral nerve injury (Rasband et al. 2001). dition,Ca2+ channelsalsoplayakeyroleinthefunction Substances like PGE2 can sensitize nociceptive sen- of central neurons involved in nociceptive processing. sory neurons by reducing activity in Kv channels. The end result of these findings is that Cav2.1 (P/Q- + Kv1.4, an A-type K channel, is expressed in sen- type), Cav2.2 (N-type), and Cav3.x (T-type) calcium sory neurons of small size, that co-express the cap- channels have been validated as useful targets for the + saicin channel TRPV1 and the TTX-R Na channel treatment of pain (reviewed by Bourinet and Zamponi Nav1.8andarepresumablypolymodalnociceptorneu- 2005). rons (Rasband et al. 2001). Kv1.1 and Kv1.2 chan- nels are also expressed in small DRG neurons and ge- netic studies have linked the lack of Kv1.1 channels HCN Channels with thermal hyperalgesia. Kv7 (also named KCNQ) The currents carried by hyperpolarization activated, channels, responsible for M-type K+ currents, are also cyclic nucleotide gated channels (HCN) have been present in nociceptive sensory neurons and pharmaco- termed If, Ih or Iq and are poorly selective K+ currents logical activation of these channels inhibits responses activatedby membranehyperpolarization.Thecurrent to algesic substances in animal models of pain (Pass- reverses at membrane potentials of about -25 mV and more et al. 2003). Finally, activation of small conduc- is inwardly directing at rest. Ih currents contribute to tance calcium activated K+ channels and ATP sensi- the resting membrane potential, inputconductanceand T tive K+ channels has been also implicated in antinoci- subthreshold membrane oscillations in many types of ception. Kir3.2 knockout and Kir3.3 knockout mice neurons(Robinson and Siegelbaum 2003).HCNchan- display hyperalgesia to elevated temperatures (>50˚C) nels, particularly HCN1 and HCN2, are abundantly suggesting implication of G-protein-gated K+ chan- expressed in sensory neurons. Inflammatory media- nels in thermal nociception. These modulatory effects tors, such as serotonin, raise intracellular cAMP lev- appear to be occurring at the level of the spinal cord els, which, in turn, increase I h current by binding to rather than at the periphery. the HCN channel, shifting its voltage dependent acti- vation to less negative potentials (reviewed by Robin- Two-pore Domain K+ Channels (KCNK) son and Siegelbaum 2003). Likewise, the amplitude of In addition to their role as cellular sensors, these chan- I h currents in DRG neurons increases markedly fol- nels, responsible for leak K+ currents, are key elements lowing spinal nerve ligation or chronic compression of in the regulation of background excitability. As such, the ganglion (Yao et al. 2003). Furthermore, pharma- they are thought to play an important role in triggering cological blockade of HCN activity with the specific ectopic discharges associated with chronic pain con- inhibitor ZD7288 reduces the spontaneous ectopic ac- ditions. tivity secondary to nerve injury and reverses abnormal hypersensitivity to light touch. These results suggest Ca2+ Channels that abnormal expression of HCN channels may be an Voltage activated Ca2+ channels are channels with important factor in the hyperexcitability secondary to steeply voltage dependent gates that open in response peripheral nerve injury. 2526 Transduction and Encoding of Noxious Stimuli

in the parent axon. This integration will determine the frequency and firing pattern of the discharge of prop- agated nerve impulses traveling to the CNS along the complete axonal path of the sensory ganglion neuron. The differences in membrane properties between sub- classes of nociceptive neurons are reflected in the conduction velocity and the shape of propagated ac- tion potentials at the parent axon and soma, far away from the peripheral endings. C nociceptive axons have longer duration APs and AP undershoot durations than low threshold mechanosensory axons (Koerber and Mendell 1992). Further differences in axonal spike duration and post-spike excitability are noticed be- tween classes of nociceptors (Lawson 2002), possi- bly influencing the pattern and frequency of their im- pulse discharge. The soma of the various classes of nociceptive neurons also possesses a number of spe- cific membrane characteristics. Neurons tentatively Transduction and Encoding of Noxious Stimuli, Figure 5 (A) Propa- gation of nerve impulses at the peripheral branches of nociceptor fibers. identified as polymodal have slow somatic action po- The stimulus extends to various branches where it generates propa- tentials with a hump in the falling phase and do not gated action potentials that travel centripetally. These action potentials present inward rectification in response to hyperpo- may collide at the branching points and this determines the final firing frequency in the parent axon (Modified from Weidner et al. 2003). (B, larizing pulses, while low-threshold mechanosensory C) Nerve terminal impulses recorded from nociceptors endings in the neurons produce short-lasting action potentials and cornea, before (B) and after (C) local application of lidocaine. The local have a prominent inward rectification (Lawson 2002). anesthetic blocks the regenerative nerve impulse that normally occurs These data further suggest that nociceptive neurons in the terminal (transducing) region of the branch (b) and only impulses + + passively propagated from neighbor endings are recorded (c). possess a specific set of voltage activated Na ,K and Ca2+ channels that confer distinct electrical properties on them and ultimately determine theirexcitability and Electrical Activity in Peripheral Terminal Arborizations pattern of impulsefiring in responseto peripheralstim- Parentsensoryaxonsofnociceptorsbranchextensively uli. in the peripheral territory. The distribution of the vari- It is worth noticing that the electrical behavior of no- oustransduction and voltage gatedchannelsispresum- ciceptor neurons is profoundly influenced by previ- ably non-homogeneous among the terminal branches ous history. Repeated stimulation can transiently mod- of the various subclasses of nociceptor fibers and per- ify their excitability, through changes in some of the haps even between branches of a single neuron. It is ionic mechanisms associated with the codification and conceivable that in nociceptors, each terminal branch propagation of nerve impulses, contributing to fatigue of an axonal arborization acts as an independent site and/orsensitization(Serraetal.1999).Similarchanges for transduction and generation of action potentials. have been observed after nerve damage. This plasticity Action potentials of nociceptor branches travel cen- isimportantin understanding the altered excitabilityof tripetally at a conduction velocity that is below that of nociceptor neurons following injury. the parent axon (Weidner et al. 2003). When arriving Conclusions at a branching point, impulses of the fastest branches willusuallytravelantidromicallyandinvadetheslower Electrophysiological, pharmacological and molecu- branch, transiently changing itsexcitabilityor evenoc- lar evidence suggests that nociceptor neurons pos- cluding the generation of action potentials (Fig. 5). In sess multiple mechanisms for detection, amplification polymodal nociceptors, antidromic action potentials and encoding of input signals. These mechanisms will invade the terminals due to the high density of TTXr mediate transduction of the various forms of stim- Na+ channels present in their membrane (Brock et al. ulating energy and also modulate the input signal 1998). at the successive steps of the transduction and en- coding processes. Different types of stimuli may in- Impulse Firing in Parent Axons and Soma teract at threshold or subthreshold levels to produce Impulses generated at the endings progress centrally propagated responses. Short- and long-term modu- through terminal branches of different length, conduc- latory mechanisms will further modify the final re- tion velocity and possibly duration of their refractory sponse characterized by a discharge of nerve impulses and supernormal periods, becoming finally integrated of a given frequency, time course and firing pattern. Transduction and Encoding of Noxious Stimuli 2527

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headache (> 15 days per month) that developed gradu- Transforaminal Interbody Fusion allyovertimefromapre-existing,well-definedmigraine  TLIF headache. Headache is longer than 4 hours per day, can include a mixture of autonomic and tension-type symp- toms, and symptoms have progressed with increasing Transforaminal Steroids frequency and decreasing severity over at least three months.  Lumbar Transforaminal Injection of Steroids  Chronic Daily Headache in Children

Transformed Migraine  Chronic Daily Headache in Children Transganglionic Transport  Transformed Migraine Headache

Definition Transformed Migraine Headache Oneofthetracttracingmethods,e.g.aneuraltracertaken up by a peripheral axon or branches of primary afferents Definition istransportedcentripetallyandthencentrifugallytotheir Classification proposed by Silberstein et al (1994), central terminals. describing a subtype of chronic daily or near daily  Trigeminal Brainstem Nuclear Complex, Anatomy Transient Headache and CSF Lymphocytosis 2529

Characteristics Transgene HaNDL is a transient syndrome characterized by severe Definition headache, focal neurological symptoms and CSF lym- phocytosis (IHS 2003; for review see Pascual and Valle Any gene inserted into a vector that is expressed in cells 2003). in vitro or animals in vivo following vector-mediated The HaNDL syndrome was first described by Bartleson transduction. et al. (Bartleson et al. 1981). Until now about 100 cases  Opioids and Gene Therapy of HaNDL havebeen published. Fiftypatientshavebeen reported by Gomez-Aranda et al. (Gomez-Aranda et al. 1997).BergandWilliamspresentedaseriesof7patients, Transgenic Knockout Mice as well as a systemic review of the literature (Berg and Williams 1995). Definition Age of onset of HaNDL ranges between 7 and 50 years, withameanof27years.HaNDLismorefrequentinmen, Genetically engineered null mutant mice. Via blastocyst with a male to female ratio of 3:1 (Berg and Williams microinjection of transgenic (i.e. possessing an altered 1995; Gomez-Aranda et al. 1997). DNA sequence) embryonic stem cells, mice can be cre- Approximately 25–30% of patients report a viral-like ated that lack all expression of a particular gene. These illness 2–3 weeks before the onset of HaNDL. Typi- mice can be evaluated for their altered pain sensitivity cal symptoms are cough, rhinitis, diarrhea and fatigue compared to „wild-type“ mice, and the function of the (Gomez-Aranda et al. 1997). missing gene/protein inferred. The timing between the headache and neurologic  Heritability of Inflammatory Nociception deficit is variable. In some patients the initial symptom  NerveGrowthFactorOverexpressingMiceasModels is headache, in others neurologic deficits occur first. In of Inflammatory Pain some patients neurologic deficits with CSF lymphocy- tosis can occur without a severe headache (Oldani et al. 1998). Transgenic Mice Headache is moderate to severe, pulsating or throbbing and mostly bilateral. In some patients the headache is  NerveGrowthFactorOverexpressingMiceasModels unilateral and localized contralateral to the neurologic of Inflammatory Pain symptoms.Durationofheadacherangesbetween1hand 1week,onaverage19h(Gomez-Arandaetal.1997).Ac- companying symptoms are nausea and vomiting, photo- Transient Headache and CSF and phonophobia. Neurologic signs usually consist of hemiparesis, Lymphocytosis hemisensory symptoms or aphasia. Sensory symp- ZAZA KAT S A R AVA,HANS-CHRISTOPH DIENER toms are more frequent than motor signs. Pure motor T Department of Neurology, University Hospital of aphasia is the most frequent speech disorder followed Essen, Essen, Germany by global aphasia and pure sensory aphasia (Gomez- [email protected] Aranda et al. 1997). Visual symptoms arerare. Thefocal neurologic symptoms usually evolve progressively, in Synonyms some cases, however, suddenly. The deficits are tran- sient, lasting from 5 minutes to hours and at most 3 Migraine With Pleocytosis, Pseudomigraine With Lym- days. Atypical cases with longer duration up to a week phocyctic Pleocytosis have been described. The recovery is always complete. Definition Routine blood and immunological tests are usually normal. Two exceptional cases associated with a cy- The International Headache Society proposed the fol- tomegalovirus infection have been reported (Ferrari lowing diagnostic criteria for HaNDL (IHS 2003): et al. 1983; Richert et al. 1987). The examination of a) Moderate or severe  headache cerebrospinal fluid reveals a lymphocytic pleocyto- b) Cerebrospinal fluid pleocytosis with lymphocytic sis (range 10–760/μl) and increased total protein. In predominance (greater than 15 cells/μl) and nor- 50% of the cases an elevated CSF pressure has been mal neuroimaging, CSF culture and other tests for measured (Berg and Williams 1995; Gomez-Aranda et etiology al. 1997). Immunological, bacterial and viral studies c) Headache occurs at timeofCSFpleocytosis produce normal results. d) Episodes of headache and neurological deficits last Electroencephalographyreveals a unilateral focal slow- < 3 months. ing during the acute HaNDL phase in up to 70% of the 2530 Transient Receptor Potential patients (Berg and Williams 1995; Gomez-Aranda et al. References  1997). In 10% EEG slowing was observed bilaterally 1. Bartleson JD, Swanson JW, Whisnant JP (1981) A Migrainous (Gomez-Aranda et al. 1997). The changes normalized Syndrome with Cerebrospinal Fluid Pleocytosis. Neurology again after the symptomatic period. 31:1257–1262 2. Berg M, Williams L (1995) The Transient Syndrome of Headache Cranial computed tomography, as well as cranial with Neurologic Deficits and CFS Lymphocytosis. Neurology magnetic resonance imaging, is usually normal. In 45:1648–1954 a few patients nonspecific small areas of high signal 3. Caminero AB, Pareja JA, Arpa J et al. (1997) Migrainous in T2-weighted images have been observed (Berg and Syndrome with CSF Pleocytosis. SPECT Findings. Headache 37:511–515 Williams 1995; Gomez-Aranda et al. 1997). Very re- 4. Dalton M, Newton RW (1991) Aseptic Meningitis. Dev Med cently, in one patient, a diffusion weighted MRI could Child Neurol 33:446–451 be performed during acute HaNDL, which did not 5. Ferrari MD, Buruma OJ, van Laar-Ramaker M et al. (1983) A reveal diffusion changes (Gekeler et al. 2002). Migrainous Syndrome with Pleocytosis. Neurology 33:813 6. Fuentes B, Diez Tejedor E, Pascual J et al. (1998) Cerebral Blood Single photon emission computed tomography has Flow Changes in Pseudomigraine with Pleocytosis Analyzed by been suggested to be the most informative neuroimag- Single Photon Emission Computed Tomography. A Spreading ing technique. A focus of decreased tracer uptake has Depression Mechanism? Cephalalgia 18:570–573, discussion been detected during the acute phase, which becomes 531 7. Gekeler F, Holtmannspotter M, Straube A et al. (2002) Diffusion- normal several days after recovery (Caminero et al. Weighted Magnetic Resonance Imaging during the Aura of Pseu- 1997; Fuentes et al. 1998). domigraine with Temporary Neurologic Symptoms and Lympho- Cerebral angiography is usually not informative. In the cytic Pleocytosis. Headache 42:294–296 8. Gomez-Aranda F, Canadillas F, Marti-Masso JF et al. (1997) vast majority of patients studied no changes could be Pseudomigraine with Temporary Neurological Symptoms found. In some patients inflammation like processes in and Lymphocytic Pleocytosis. A Report of 50 Cases. Brain the wall of the opercular arteries have been detected, and 120:1105–1113 in some patientsnew episodesof HaNDL were triggered 9. IHS (2003) Headache Classification Committee of the Interna- tional Headache Society. Classification and Diagnostic Crite- by the angiography, therefore it has to be avoided. ria for Headache Disorders, Cranial Neuralgias and Facial Pain. The pathophysiology of HaNDL is still unclear. There Cephalalgia (in press) are some obvious similarities to  migraine with aura. 10. Mayer SA, Yim GK, Onesti ST et al. (1993) Biopsy-Proven Iso- However, only few patients with HaNDL report a lated Sarcoid Meningitis. Case Report. J Neurosurg 78:994–996 11. Oldani A, Marcone A, Zamboni M et al. (1998) The Transient history of migraine. The duration of the focal neuro- Syndrome of Headache with Neurologic Deficits and CSF Lym- logical symptoms in HaNDL is longer than in migraine phocytosis. Report of a Case without Severe Headache. Headache with aura. The most important difference between the 38:135–137 HaNDL and migraine is the CSF pleocytosis. HaNDL 12. Pal GS, Baker JT, Humphrey PR (1987) Lyme Disease Presenting as Recurrent Acute Meningitis. Br Med J (Clin Res Ed) 295:367 has also been separated from other diseases such as 13. Pascual J, Valle N (2003) Pseudomigraine with Lymphocytic familial hemiplegic migraine or progressive cerebellar Pleocytosis. Curr Pain Headache Rep 7:224–228 ataxia. 14. Richert JR, Potolicchio S Jr, Garagusi VF et al. (1987) Cy- tomegalovirusEncephalitisAssociated withEpisodic Neurologic There are several infectious diseases that can cause Deficits and OKT-8+ Pleocytosis. Neurology 37:149–152 headache, focal neurologic symptoms and CSF pleocy- 15. Roldan-Montaud A, Jimenez-Jimenez FJ, Zancada F et al. (1991) tosis.Mollaret’smeningitisischaracterizedbyrecurrent Neurobrucellosis Mimicking Migraine. Eur Neurol 31:30–32 episodes of aseptic meningitis with headache and symp- toms of meningeal irritation. However, focal neurologi- cal symptoms are not typical for Mollaret’s meningitis. Transient Receptor Potential Furthermore, the pleocytosis in Mollaret’s meningitis is a mixture of lymphocytes, polymorphonuclear- and Definition large ‘Mollaret’s’ cells. HaNDL has to be separated from further infectious Transient change in electrical potential across the cell conditions such as Lyme disease (Pal et al. 1987), neu- membrane, for example, induced by activation of a TRP rosyphilis (Berg and Williams 1995), neurobrucellosis receptor. (Roldan-Montaud et al. 1991), mycoplasma infection  TRPV1 Receptor, Species Variability (Dalton and Newton 1991), granulomatous meningitis (Mayer et al. 1993), and secondary cytomegalovirus encephalitis associated with human immunodeficiency Transient Receptor Potential Family of virus (HIV) infection (Richert et al. 1987). HaNDL is always a self-limiting disorder. Therefore, Ion Channels the therapy is restricted to symptomatic treatment with analgesics and antiemetics. No preventive treatment is Definition needed. The mammalian transient receptor potential (TRP) ion channels are named after the role of these channels in Drosophila phototransduction. They are encoded by Transition from Acute to Chronic Pain 2531 at least 21 different channel genes. The TRP channel have been made when following patientsaftersurgeryor primary structures predict six transmembrane domains, trauma; and severe early pain after thoracotomy (Katz et with a pore domain between the fifth and sixth segments, al. 1996) and orthopaedic trauma (Gehling et al. 1999) and both the C- and N-terminiare locatedintracellularly. predicts development of chronic pain states. The mammalian TRP channel family is comprised of three subfamilies, including TRPC, TRPV and TRPM. Risk Factors for Transition to Chronic Pain States The family members are at least 25% homologous In2000,PerkinsandKehletpublisheda  meta-analysis within their amino acid sequences. Most of the chan- of the predictive factors of chronic pain after surgery nels are non-selective to cations, allowing sodium and (Perkins and Kehlet 2000). They identified a number of calcium to flow in and depolarize neurons. The most significant risk factors for this transition, which include well-characterized TRP channels in DRG neurons are type of surgery, preoperative, intraoperative and postop- the vanilloid family of TRPV1–4 channels, which are erative factors: activated by a range of heat and/or warm temperatures. TRPV1 is the prototype vanilloid channel and is acti- Type of Surgery vated by noxious heat, acidic pH and the alkaloid irritant After lower limb amputation phantom limb pain occurs capsaicin. Additional TRP channels in DRG neurons in 30–81% and stump pain in >50%. Post-thoracotomy are TRPM8, which is activated by cool temperatures pain syndrome (PTPS) occurs in >50% of patients. and menthol, and ANKTM1, which is activated by Breast surgery can give rise to chest wall, scar, breast mustard oil derivatives and may be activated by cold. or shoulder pain in 11–57% of patients, and phantom  Immunocytochemistry of Nociceptors  breastpain in 13–24%;post-mastectomypainsyndrome TRPV1 Receptor, Species Variability (PMPS) has an overall incidence of 50% at one year (Kwekkeboom 1996). Gallbladder surgery carries a risk between 3 and 56% of post-cholecystectomy syndrome Transient Receptor Potential Vanilloid 1 (PCS). (TRPV1 or VR1) Receptor Preoperative Factors  TRPV1 Intense preoperative pain increases the incidence of phantom limb pain (from 33% to 72%) (Nikolajsen et al. 1997; Krane and Heller 1995). Preoperative risk factors for PCS include ‘psychologic vulnerability’, fe- Transition from Acute to Chronic Pain male gender and long-standing preoperativesymptoms. Other factors are repeat surgery and issues of compen- SARAH J. HARPER,STEPHAN A. SCHUG sation. Preoperative epidural pain control may decrease Royal Perth Hospital and University of Western the risk of chronic pain after amputation (Schug 2004, Australia, Perth, WA, Australia Bach et al. 1988). [email protected] T Intraoperative Factors Synonyms Technicalissuesofthesurgery,includingthesurgicalap- Pain Progression; Pain Chronification; Central sensiti- proach and the risk of nerve injury, are important here. sation Video-assisted-thoracoscopic lung surgery reduces the risk of PTPS compared to open lung resection. Position Definition of the incision for thoracotomy may influence the inci- It is now well established that chronic pain can develop dence of PTPS. Intraoperative epidural analgesia seems as the consequence of repeated or severe episodes of to reduce the risk of PTPS. The incidence of PMPS may acute pain, e.g. in the context of trauma, surgery or acute be increased by: breast-conserving surgery, immediate painful illness. This progression is most likely to be the insertion of implants, extent of axillary dissection and consequence of central nervous processes, commonly damage to the intercostobrachial nerve. called central  neuroplasticity or sensitisation. Early Postoperative Factors Characteristics Stump pain at one week post amputation correlates with It is well recognised that chronic pain states often follow theriskofphantompain.Intensityofacutepostoperative an acutely painful stimulus such as surgery or trauma. pain is an independent predictor for PTPS and PMPS. A large study of over 5000 patients referred to chronic Intercostal nerve dysfunction (loss of the superficial ab- pain clinics in the UK, revealed that 22.5% of these pa- dominal reflex) is associated with more acute, subacute tients had developed their pain after surgery, and 18.7% and chronic pain. Adjuvant postoperative radiotherapy after trauma (Crombie et al. 1998). Similar observations to the breast increases the risk of development of PMPS. 2532 Transition from Acute to Chronic Pain

Late Postoperative Factors by the post-synaptic cell. By diffusing back to the Long-term stump pain predicts long-term phantom limb pre-synaptic membrane, these cause an increased trans- pain (Nikolajsen et al. 1997). More severe or prolonged mitter release in response to each pre-synaptic action acute pain in the postoperative period as well as postop- potential. Subsequently, calcium-dependent enzymes erative complications, commonly leading to increased are activated, such as protein kinases A and C (PKA,  nociception, significantly predict the development of PKC) and calcium/calmodulin kinase, leading to phos- chronicpainaftersurgery(Katzetal.1996,Gehlingetal. phorylation of membrane proteins including receptors 1999).Otherrelevantfactorsareradiotherapyandneuro- and ion channels. This makes the post-synaptic cell toxic chemotherapy, but also psychological factors such more excitable, and upregulation of AMPA receptors as anxiety, depression, neuroticism and psychological and growth of dendrites/spines on the post-synaptic cell vulnerability. occurs. The overall result is LTP, which can last from one hour Mechanisms for the Transition from Acute to Chronic to several months. It can be slowed or prevented from Pain occurring in vitro by NMDA antagonists, early cooling The development of chronic pain is based on the phe- or PKC inhibitors, but in contrast to wind up cannot be nomenon of central neuroplasticity. Disruption of the reversed. normalspecialisationofthesomatosensorysystemleads to increasing mismatch between stimulus and response. Recruitment The underlying mechanisms are not fully elucidated Chronic inflammation and nerve injury have an ef- yet, however, the physiological principles have been fect on the presence and distribution of voltage-gated reviewed in detail (Pockett 1995). The implications for sodium channels, which can become concentrated in the development of chronic pain as a separate disease areas of injury and produce ectopic discharges. Studies entity have been summarised recently by Siddall and have shown that neurone-specific sodium channels Cousins (Siddall and Cousins 2004). Some of these become concentrated in neurones proximal to a site mechanisms are presented in the following: of nerve injury, and play a role in the  hyperalgesia and  allodynia of chronic pain states. Not all sensory Wind Up neurons are active all the time, and this  peripheral A progressive increase in the number of action poten- sensitisation will ‘recruit’ dormant nociceptors, thus tials elicited per stimulus occurs in dorsal and ventral increasing the receptive fields of dorsal horn neurons horn neurons when the stimulus exceeds 0.5 Hz. Above and increasing the intensity and area of pain (Mannion this frequency, the post-synaptic depolarising responses and Woolf 2000). summate to produce a cumulative  depolarisation,re- sulting in a burst of action potentials, instead of a single Immediate Early Gene Expression action potential, in response to each stimulus. It is medi- Immediate early genes are a family of genes (e.g. c-fos, ated via N-methyl-D-aspartic acid (NMDA) glutamate c-jun)thatsharethecharacteristicofhavingtheirexpres- receptors and therefore blocked and reversed by NMDA sion rapidly and transiently induced upon stimulation antagonists.  Wind-up lasts as long as ventral horn cell of neuronal and non-neuronal cells (Caputto and Guido depolarisation, i.e. about 60 seconds. 2000). Damaged sensory neurones may undergo altered geneexpression,suchthattheyreleaseadifferenttypeof Long Term Potentiation neurotransmitter. The release of neurotransmitters usu- Repeated episodes of wind-up may trigger  long-term ally associated with noxious stimuli, such as substance potentiation (LTP). It was first studied in the hippocam- P, may contribute to  central sensitisation. pus and is now known to occur in visual, sensorimotor Achange in gene expression can also lead toupor down- and pre-frontal cortex, as well as in the spinal cord. Its regulation of ion channels leading to changes in cellular mechanism is complex, but in essence high-frequency excitability. pre-synaptic activity causes a pre-synaptic glutamate release, which activates α-amino-3-hydroxy-5-methyl- Excitotoxicity 4-isoxazole propionic acid (AMPA) receptors. AMPA  Excitotoxicity is a phenomenon that was first de- receptor activation opens ion channels allowing post- scribed by Olney in the seventies (Olney et al. 1972). synaptic depolarisation. If the depolarisation reaches It involves the activation of glutamate receptors in the a certain threshold, a magnesium-dependent block of central nervous system (CNS). Glutamate, an excita- NMDA receptors is released, and these then open their tory amino acid, activates different types of ion channel associated ion channels. There is an overall influx of forming receptors to develop their essential role in the calcium ions which triggers additional calcium release functional activity of the brain. However, high concen- from intracellular calcium stores. The intracellular cal- trations of glutamate or neurotoxins acting at the same cium rise triggers a complex chain of events, which receptors, cause cell death by apoptosis through the includes the release of one or more retrograde factors excessive activation of these receptors. Transsynaptic Changes after Peripheral Nerve Injury 2533

The physiological role of the NMDA receptor seems 15. Sureda FX (2000) Excitotoxicity and the NMDA receptor. to be related to synaptic plasticity and learning. In From EUROSIVA meeting Vienna. www.eurosiva.org/Archive/ addition, working together with G-protein coupled Vienna/abstracts/Speakers glutamate receptors, it ensures the establishment of the long-term potentiation phenomenon (LTP) described above. Research into the phenomenon has focused on Transition from Parenteral to Oral finding clinically useful NMDA receptor antagonists, Analgesic Drugs for use in both chronic pain conditions and neurodegen- erative disorders in which excitotoxicity plays a part,  such as  Parkinson’s disease and Alzheimer’s disease Postoperative Pain, Transition fromParenteral to Oral (Sureda 2000). Conclusion Translaminar Epidural Steroid Injection These mechanisms imply that chronic pathological pain may persist long after the initial noxious insult has ceased and tissue damage has healed. The process  Epidural Steroid Injections for Chronic Back Pain of synaptic plasticity and learning begins early and is difficult to reverse. It seems that untreated acute pain persisting for long periods of time can imprint Transmitters in the Descending Circuitry memory-like processes into the central nervous system (Schug 2004). Currently the recommendation is that an extended, balanced, multi-modal approach to pain  Descending Circuitry, Transmitters and Receptors management should begin in the preoperative period and continue postoperatively.

References Transmucosal 1. Bach S, Noreng MF, Tjellden NU (1988) Phantom Limb Pain in Amputees during the First 12 Months following Limb Am- Definition putation, After Preoperative Lumbar Epidural Blockade. Pain 33:297–301 Absorption across the buccal mucosa. 2. Caputto BL, Guido ME (2000) Immediate early gene expres-  Pain Control in Children with Burns sion within the visual system: light and circadian regulation in the retina and the suprachiasmatic nucleus. Neurochem Res 25:153–162 3. Crombie IK, Davies HT, Macrae WA (1998) Cut and Thrust: Antecedent Surgery and Trauma amongst Patients Attending a Transmucosal Fentanyl Chronic Pain Clinic. Pain 76:167–171 4. Gehling M, Scheidt C-E, Neibergall H et al. (1999) Persistent Definition Pain after Elective Trauma Surgery. Acute Pain 2:110–114 T 5. Katz J, Jackson M, Kavanaugh B, Sandler A (1996) Acute Pain Transmucosal fentanyl is also available as a lollipop after Thoracic Surgery Predicts Long-Term Post-Thoracotomy Pain. Clin J Pain 12:50–55 preparation (transmucosal preparation) that has been 6. Krane EJ, Heller LB (1995) The Prevalence of Phantom Limb successfully used in children. Sensation and Pain in Pediatric Amputees. J Pain Symptom Man-  Postoperative Pain, Fentanyl agement 10:21–29 7. Kwekkeboom K (1996) Postmastectomy Pain Syndromes. Can- cer Nurs 19:37–43 8. Mannion RJ, Woolf CJ (2000) Pain mechanisms and manage- ment: A central perspective. Clin J Pain 16(3 suppl):S144–156 Transmural 9. Nikolajsen L, Ilkjaer S, Kroner K et al. (1997) The Influence of Preamputation Pain on Postamputation Stump and Phantom Pain. Pain 72:393–405 Definition 10. Olney JW, Sharpe LG, Feigin RD (1972) Glutamate-induced Passing through a wall, as of the body or of a cyst or any brain damage in infant primates. J Neuropathol Exp Neurol 31:464–488 hollow structure. 11. Perkins FM, Kehlet H (2000) Chronic Pain as an Outcome  Animal Models of Inflammatory Bowel Disease of Surgery – A Review of Predictive Factors. Anesthesiology 93:1123–1133 12. Pockett S (1995) Spinal Cord Synaptic Plasticity and Chronic Pain. Anesth Analg 80:173–179 13. Schug SA (2004) Acute Pain Management – Its Role in the Transsynaptic Changes after Peripheral Prevention of Chronic Pain States. ASEAN J Anaesthesiol Nerve Injury 5:166–169 14. Siddall PJ, Cousins MJ (2004) Persistent pain as a disease entity: implications for clinical management. Anesth Analg 99:510–520  Central Changes after Peripheral Nerve Injury 2534 Traumatic Angiospasm

Traumatic Angiospasm Treatment Outcome

 Complex Regional Pain Syndromes, General Aspects  Psychological Treatment of Chronic Pain, Prediction of Outcome Traumatic Nerve Endbulb Pain

 Neuroma Pain Treatment Outcome Research

 Psychology of Pain, Efficacy Treating Pediatric Burns

 Pain Control in Children with Burns Treatment-Related Neutropenia

Treatment Adherence Definition Low white blood counts that develops after chemother- Definition apy or radiation therapy.  The extent to which patients or clients follow treatment Cancer Pain Management, Orthopedic Surgery recommendations made by the clinician, or treatment goals negotiated with the clinician.  Chronic Pain, Patient-Therapist Interaction Tremor

Treatment Alliance  Orofacial Pain, Movement Disorders

Definition The extent to which patients and clinicians agree on Tricyclic Antidepressants treatment goals and hold each other in positive regard.  Chronic Pain, Patient-Therapist Interaction MARK JOHNSTON Musculoskeletal Physician, Hibiscus Coast Highway, Orewa, New Zealand Treatment Matching [email protected]

Definition Synonyms Prescribing treatments based on specific features of TCAs; tricyclics patients that are believed to be important to outcomes. Treatments may be matched on the basis of physi- Definition cal, behavioral, or any unique individual differences Tricylic antidepressants are a group of drugs developed associated with pain and disability. and prescribed primarily as antidepressants. It was dis-  Psychological Assessment of Pain covered in the 1960s that they had an analgesic effect, which was separate from their antidepressant effect. They have since been used increasingly as an analgesic Treatment of Neuropathic Pain in managing chronic pain. TCAs consist of a 3 ring central core (Fig. 1). Their  Phantom Limb Pain, Treatment properties are related to the degree of saturation of the terminal amine. Tertiary amines available at present include; amitriptyline, clomipramine, dox- epine, imipramine and trimipramine. Some of these Treatment of Phantom Pain compounds are metabolised to active secondary amine tricylic compounds e.g. imipramine to desipramine and  Phantom Limb Pain, Treatment nortriptyline from amitriptyline. Tricyclic Antidepressants 2535

There is no evidence, or no more than dubious evidence, for the use of TCA in: acute or chronic low back pain, ‘rheumatologic pain’ (including fibromyalgia), and chronic facial pain. CombiningTCAswithotheranalgesicshasbeenrecom- mended in patients with chronic pain, but there are no good studies to support this practice. Side Effects Cardiovascular The most serious side effects of TCAs are on the car- diovascular system, where they can cause heart block, arrhythmias, and postural hypotension. TCAs slow conduction through the heart. The effect is more marked in patients with pre-existing cardiac conduction disease, particularly bundle branch block. Ischemic heart disease is frequently associated with conduction defects. Some 18% of depressed patients Tricyclic Antidepressants, Figure 1 The core chemical structure of with ischemic heart disease, treated with nortriptyline, the tricyclic antidepressants, showing the three-ring structure. Individual developed potentially dangerous sinus tachycardia or agents differ in their substitution of carbon or nitrogen in the central ring, complex arrythmias, compared with 2% in those treated and in the radicle on the amine chain. with paroxitene (Roose et al. 1998). Treating the elderly is a problem, as ischemic heart disease is common, and Characteristics as many episodes may be silent it may not be obvi- ous from the history that the patient is suffering from Mechanisms ischemic heart disease. Whereas their antidepressant action takes about 2–3 Postural hypotension is a result of α-adrenergic receptor weeks to develop, the analgesic effect of TCAs oc- blockade. Syncope can occur at any age, but it is more curs in 3–7 days. For many years, the most appealing serious in the elderly. The elderly are more prone to syn- hypothesis was that the analgesic and antidepressant cope, as part of the normal aging process. Other diseases effects are related to the block of reuptake of nore- (congestive heart failure etc.) and medication (vasodila- pinephrine and serotonin (5–HT) at spinal dorsal horn tors, diuretics etc.) may intensify the normal postural synapses. Presynaptically, TCAs inhibit the reuptake blood pressure drop. The consequences of falls are also of serotonin, norepinephrine, and to a lesser degree, more serious in the elderly. dopamine. Postsynaptic activity is variable. Amitripty- line blocks cholinergic, histamine, alpha adrenergic, Sedation muscarinic, N-methyl-D-aspartate (NMDA), substance Sedation can be a useful side effect if the patient has in- T P, and various subsets of serotonergic receptors. somnia. Sedation is caused by blockade of H1 receptors. Recent evidence from animal studies has shown that Different TCAs produce different degrees of sedation. other mechanisms may also be having antinociceptive The sedative effects may diminish after several weeks. effects. These include: modulation of the sympathetic Sexual Dysfunction nervous system, blockade of sodium channels, some anti-inflammatory effects, and mechanisms involving TCAs have all been reported to delay or prevent orgasm GABA or opioid receptors (Cohen and Abdi 2001). in both sexes. Routes of Administration Psychiatric TCAs are only administered orally. However, intra- Manic episodes may be triggered in patients with bipo- venous preparations can be obtained. lar disease. A greater concern is that of a possible sui- cide attempt using TCAs, in someone who has severe Applications depression. In large doses the cardiovascular effects can TCAs have been recommended and used in many pain be lethal. conditions, but this is not supported by the evidence. Ev- Withdrawal Syndromes idence supports their use only for: Sudden or gradual discontinuation of TCAs may cause a • diabetic neuropathy number of symptoms. These include: nausea, vomiting, • postherpetic neuralgia headache, malaise, sleep disturbance, akathisia, or para- • tension-type headache doxical behavioural activation resulting in hypomanic • prevention of migraine and tension-type headache symptoms. These effects may start within 24 to 48 hours 2536 Tricyclic-Type Antidepressants of the last dose and last up to 1 month. To reduce with- 4. O’Malley PG, Balden E, Tompkins G, Santoro J, Kroenke K, drawal symptoms, the dose should be tapered gradually; Jackson JL (2000) Treatment of Fibromyalgia with Antidepres- sants: A Meta-Analysis. J Gen Inter Med 15:659–666 if symptoms are upsetting, the dose may even be in- 5. Roose SP, Laghrissi-Thode F, Kennedy JS, Nelson JC, Big- creased a little. ger JT, Pollock BG, Gaffney A, Narayan M, Finkel MS, McCafferty J, Gergel I (1998) Comparison of Paroxitene and Serotonin Syndrome Nortriptyline in Depressed Patients with Ischemic Heart Disease. JAMA 279:287–291 Combining TCAs with selective serotonin re-uptake 6. Tomkins GE, Jackson JL, O’Malley PG, Balden E, Santoro JE inhibitors or monoamine reuptake inhibitors may pre- (2001) Treatment of Chronic Headache with Antidepressants: A cipitate a “serotonin overload syndrome”, characterised Meta-Analysis. Am J Med 111:54–63 by myoclonus, hyperreflexia, tremor, increased muscle 7. van Tulder MW, Koes BW, Bouter LM (1997) Conservative Treatment of Acute and Chronic Non-Specific Low Back Pain. tone, fever, shivering, sweating, diarrhoea, delirium, Spine 22:2128–2156 coma or death (Bodner et al. 1995). The condition is usually reversible if the drugs involved are stopped. Efficacy Tricyclic-Type Antidepressants For the treatment of chronic low back pain, a systematic review (van Tulder et al. 1997) found moderate evidence  Antidepressant Analgesics in Pain Management that TCAs are not effective for chronic LBP. There is no evidence of efficacy in acute low back pain. For  neuropathic pain, TCAs are considered ‘adjuvant analgesics’. A systematic review (McQuay et al. 1996) Tricyclics concluded that TCA are effective for the treatment of neuropathic pain: “of 100 patients ...30 will obtain  Tricyclic Antidepressants morethan50%painrelief”Evidenceisstrongestforpain relief with amitriptyline and desipramine. For  fibromyalgia, TCAs provide pain relief and im- provesleep(O’Malleyetal.2000).The NNTwas4 for Trigeminal Brainstem Nuclear Complex, the outcome ‘to obtain significant benefit’. A meta-analysis (Tomkins et al. 2001) of the outcomes Anatomy from TCAs for the treatment of chronic headache YOSHIO SHIGENAGA,ATSUSHI YOSHIDA showed an NNT of 3.2, for ‘improvement in headaches’. Department of Oral Anatomy and Neurobiology, The effect was the same for TCA and serotonin antago- Osaka University, Osaka, Japan nists,andforbothtension-likeheadachesandmigraines. [email protected], [email protected] Selection When deciding which TCA to use, the broader spectrum Definition ones, such as amitriptyline, imipramine and nortripty- line, have greater efficacy than the selective re-uptake The trigeminal brainstem nuclear complex in mam- blockers. Nortriptyline may be the best as it has less se- mals is generally recognized to include the principal dation, less postural hypotension and less anticholiner- nucleus (Vp), the spinal nuclear complex (Vsp; some- gic effects. times also termed the spinal tract nucleus), and the   Antidepressants in Neuropathic Pain mesencephalic nucleus (Vmes). It extends through  Drugs Targeting Voltage-Gated Sodium and Calcium the pons and medulla from the C2 spinal segment and Channels upward through the mesencephalon. In a caudoros-  Drugswith Mixed Action and Combinations, Empha- tral direction, these nuclei are the Vsp, Vp, and Vmes sis on Tramadol (Fig. 1). Three further divisions of the Vsp are differ-  Postoperative Pain, Postamputation Pain, Treatment entiated (Olszewski 1950): the subnuclei caudalis (Vc) and Prevention (Fig. 1e), interpolaris (Vi) (Fig. 1d), and oralis (Vo) (Fig. 1b, c). The Vmes differs from the other nuclei in that it contains cell bodies of primary afferents inner- References vating jaw muscle spindles or periodontal ligaments. 1. Bodner RA, Lynch T, Lewis L, Kahn D (1995) Serotonin Syn- drome. Neurology 45:219–223 Characteristics 2. Cohen SP, Abdi S (2001) New Developments in the Use of Tri- cyclic Antidepressants for the Management of Pain. Curr Opin The Vp and Vsp integrate the trigeminal afferent system Anaesthesiol 14:505–511 that is organized to serve the  exteroceptive, interocep- 3. McQuay HJ, Tramer M, Nye BA, Carroll D, Wiffen J, Moore RA (1996) A Systematic Review of Antidepressants in Neuropathic tive,andproprioceptivesensoryfunctionsoftheoraland Pain. Pain 68:217–227 craniofacialstructures, butalso receive projectionsfrom Trigeminal Brainstem Nuclear Complex, Anatomy 2537

Trigeminal Brainstem Nuclear Complex, Anatomy, Figure 1 Camera lucida drawings illustrating the distribution of horseradish peroxidase (HRP) reactions produced at different levels of the trigeminal brainstem nuclear complex after injections of HRP into the lower tooth pulps. (a) to (e) are arranged rostrocaudally. BC, brachum conjunctivum; S, nucleus of solitary tract; SO, superior olivary nucleus; Vtr, spinal trigeminal tract; VII, facial nucleus; 5, trigeminal motor nerve; 7, facial nerve. D-L, T dorsal-lateral. Scale bar = 0.5 mm. (Modified from Fig. 1 in Shigenaga et al., 1986c). the facial, glossopharyngeal and vagus nerves and upper Nucleus Principalis (Vp) cervical nerves. The trigeminal spinal tract (Vtr) is somatotopically or- This is divided into a subnucleus dorsomedialis (Vpd) ganized, with fibers of the ophthalmic, maxillary, and and a subnucleus ventrolateralis (Vpv; Fig. 1a). The mandibular divisions lying successively more dorsally. Vpv extends further caudally than the Vpd, to the rostral This dorsoventral arrangement is also applicable to the pole of the facial nucleus. The caudal limit of Vpd corre- facialregionoftheVpandVsp,whiletheintraoralrepre- spondstothecaudalpoleofthetrigeminalmotornucleus sentation is organized in a complex manner (see below) (Vmo). The neurons are densely packed and have a uni- (Shigenaga et al. 1986a; Shigenaga et al. 1986b; Shige- form appearance, with small and medium-sized, round naga et al. 1989b). or oval cell bodies. The Vpd is distinguished by the Primary afferent projections are not identical at each compact aggregation of its cells, although caudally it level, as the density of terminals varies along differ- becomes loosely arranged (Shigenaga et al. 1986b). ent nuclei, or in different parts of the same nucleus The central projections of primary afferents have been (Tsuru et al. 1989). The individual nuclei are connected examined using the techniques of  transganglionic by ascending and descending internuclear pathways transport and intraaxonal labeling of horseradish per- (Nasution and Shigenaga 1987). oxidase (HRP). The Vpd receives a projection from 2538 Trigeminal Brainstem Nuclear Complex, Anatomy trigeminal primary afferents innervating intraoral struc- The Vo.ris characterized by large  multipolar cells and tures, but both the intraoral and facial afferents project merges medially with the lateral reticular formation. to the Vpv (Shigenaga et al. 1986b). Both the subnuclei More caudally, two regions represent subgroupings, a receive mesencephalic afferent projections (Shigenaga ventrolateral region (Vo.c) and a dorsomedial region et al. 1988; Shigenaga et al. 1989a). Tooth pulp afferents (Vo.dm, Fig. 1c). The Vo.dm is composed mainly of terminate in the Vpd in the cat (Shigenaga et al. 1989b; small, compactly arranged cells and merges with the Westrum et al. 1981), and in the Vpd and Vpv in the rat ventrolateral border of the solitary nucleus. In the cat, (Marfurt and Turner 1984). this subdivision is present between the levels corre- Intraaxonal labeling shows that stained axons (central sponding to the facial nucleus, whereas in the rat it processes) of primary afferents in the Vtr ascend and continues without change of structure caudally into the descend (bifurcating fibers), or descend without bifur- Vi. The Vo.c is composed of oval- or spindle-shaped cation (descending non-bifurcating fibers) (Tsuru et al. small cells, triangular or fusiform medium-sized cells, 1989; Hayashi 1985). The ascending fiber and the de- and large multipolar cells. The large cells are sparsely scending fiber give off axon collaterals mainly in the Vp scattered throughout this subdivision (Shigenaga et al. and the Vsp, respectively. 1986b). The Vo.r and Vo.dm receive projections from At the electron microscopic level (Bae et al. 2003), primary afferents innervating intraoral structures as all pulpal afferent boutons in rats contain clear, round well as from mesencephalic primary afferents (Shige- vesicles (S-type), and make synaptic contact with naga et al. 1989a), while facial afferents project to the non-primary dendrites with  asymmetric junctions. Vo.c. A dorsoventral organization is not apparent in the Approximately one-third of the boutons show charac- Vo.r and Vo.dm. In cats, pulpal afferents terminate in teristic glomeruli, in which synaptic contact is made the Vo.r and Vo.dm, where the upper and lower teeth with small dendrites as well as with other axon ter- are represented in a mediolateral sequence, and projec- minals. The  synaptic glomerulus has an important tions from the anterior to posterior teeth are organized role to activate multiple second-order neurons at the in a ventrolateral to dorsomedial sequence, with an same time. The presynaptic axon terminals contain extensive overlap in projections from adjoining teeth  pleomorphic vesicles and form symmetric contacts (Shigenaga et al. 1989b). with the postsynaptic membrane. The presynaptic At the electron microscopic level (Bae et al. 2003), boutons are immunoreactive for GABA. These ultra- synaptic organization of rat pulpal afferent boutons in structural features are also common in axon terminals the Vo differs from that in Vp, in that the number of from low-threshold mechanoreceptive afferents. postsynaptic elements per bouton and the frequency The distribution of cell bodies of trigeminothalamic of axoaxonic contacts are lower in the Vo, indicating neurons has been mapped in cats with the  retrograde less frequent synaptic glomeruli. These ultrastruc- labeling technique (Shigenaga et al. 1983). It was found tural features are common to those of low-threshold that most Vpv neurons project of the contralateral tha- mechanoreceptive afferent terminals in the Vp and Vo lamus to the nucleus ventralis posteromedialis (VPM) in cats. via the crossed ventral tract, while most Vpd neurons Vo neurons, especially in Vo.r and Vo.dm,send few ax- project to the ipsilateral VPM via the uncrossed dorsal ons to the VPM in cats (Shigenaga et al. 1983), while a tract. Thus sensory information from the intraoral struc- considerable number of Vo.r neurons project to the CL tures is mediated through both crosswed (via Vpv) and of the intralaminar complex. uncrossed (via Vpd) pathways, whereas facial sensory There are, however, species differences, and a signif- information is mediated via Vpv by a single crossed icant projection to VPM might exist in the rat (see pathway, although in the rat most Vpd neurons project  Trigeminal Brainstem Nuclear Complex, Physiol- into the crossed pathway. The axons of the crossed ogy). In addition, the Vo.r and Vo.dm contain pre- pathway give off collaterals in the central lateral nu- motoneurons projecting to either jaw-closing or jaw- cleus (CL) of the intralaminar complex (Shigenaga opening regions of the motor nucleus (Yoshida et et al. 1983). An  intracellular labeling study in cats al.1994). Although many neurons respond to light me- (Yoshidaetal. 1998) hasshown thattheVp also contains chanical stimulation of intraoral structures, some are  local-circuit cells whose axon collaterals terminate activated by noxious stimuli. These nociceptive neurons in the jaw-closing region of the Vmo and the lateral send their axon collaterals to the jaw-closing region of reticular formation. the V motor nucleus, suggesting that they may be in- volved in a reflex circuit that modulates jaw-closing Subnucleus Oralis (Vo) alpha-motoneurons. This extends from the caudal tip of the facial nucleus to the level a little posterior to the caudal end of Vmo and Subnucleus Interpolaris (Vi) thus, the rostral half of the Vo(termed Vo.r)is situated in This lies between the Vo and Vc and ends a little cau- the region dorsomedial to the Vpv (Fig. 1b). Its caudal dal to the obex, and is composed of three neural popula- limitcorrespondsto the rostralpole ofthe facialnucleus. tions with small, medium, and large cells. Its dorsome- Trigeminal Brainstem Nuclear Complex, Anatomy 2539

Trigeminal Brainstem Nuclear Complex, Anatomy, Figure 2 Schematic drawings of the oral and facial representation in laminae I and II of the medullary and upper cervical dorsal horns. A series of concentric bands (a)-(e) depicting the ”onionskin” representation is shown in the drawing of a cat’s face and mouth. In a three-dimensional diagram of the medullary and upper cervical dorsal horns, intraoral divisions are marked by O and numbers indicated on the right side show distance in millimeters rostral or caudal (-) to the obex. Each terminal zone of the trigeminal afferent branches examined is filled in in the right column, where b and m indicate presumed terminal zones of the facial branch of the buccal nerve and the most anterior branch of the mental nerve, respectively. The ophthalmic (V1), maxillary (V2), mandibular (V3) divisions of the trigeminal nerve are illustrated by straight lines, oblique lines, and black dots, respectively. ai, inferior alveolar nerve; as, superior alveolar nerve; at, auriculotemporal nerve; b, buccal nerve; c, cornea; f, frontal nerve; io, infraorbital nerve; T l, lingual nerve; m, mental nerve; my, mylohyoid nerve; p, palatine nerve; z, zygomatic nerve. (Adapted from figure 13 in Shigenaga et al. 1986a). dial margin, however, contains ovoid- or spindle-shaped jection sites are confined to the caudal levels of Vi. small or medium-sized cells, where pulpal afferents ter- They are in the most lateral part of the nucleus, with minate in cats (Shigenaga et al. 1986b). an extensive overlap in projections, save for the deep The projection pattern of primary afferents in the Vi is temporal nerve, which projects to the interstitial nucleus organized in a similar fashion to that in the Vpv, with the (see below). exception of lingual and pulpal afferents, which do not Similar to the Vpv, the Vi neurons project to the con- terminate in the Vpv in the cat (Shigenaga et al. 1986b; tralateralVPM,butnottotheCL(Shigenagaetal.1983). Shigenaga et al. 1989b). The Vi neurons in Vi/Vc transition zone in rats project The pulpal projections from the cat‘s upper and lower to the nucleus submedius (Sm) of the thalamus (Yoshida teeth are represented in the medial Vi (Fig. 1d) with a et al. 1991). topographic fashion, similar to that found in the Vo.r and Vo.dm(Shigenaga et al. 1989b). In addition, the Vi Subnucleus Caudalis (Vc) receives projections of primary afferents, with the cell This extends from the obex to the level of the pyramidal bodies in the trigeminal ganglion, from jaw-closing and decussation or the C2 segment. The structure resembles -opening muscles (Shigenaga et al. 1988). Their pro- closely the spinal dorsal horn, thus it is often termed 2540 Trigeminal Brainstem Nuclear Complex, Anatomy the medullary dorsal horn. Olszewski (1950) divided ical substrate for referred pain phenomena may be pro- the Vc into three laminar zones: marginalis, gelati- vided by the extensive mediolateral overlap in projec- nosus, and magnocellularis. The Rexed lamination tions from different nerve branches. Neurons in laminae scheme of the spinal dorsal horn is also applicable to III and IV project to the rostral nuclei (Nasution and Shi- the Vc, and the marginalis, gelatinosus, and magnocel- genaga 1987) and medullary reticular formation. lularis correspond to lamina I, lamina II, and laminae III/IV, respectively (Fig. 1e). In the most rostral part, cell islands of lamina I (termed interstitial nucleus) References are seen intercalated in the dorsal, lateral and ventral 1. Bae YC, Kim JP, Choi BJ et al. (2003) Synaptic Organization parts of the Vtr at the caudal levels of Vi. The detailed of Tooth Pulp Afferent Terminals in the Rat Trigeminal Sensory morphology of cells in the different laminae has been Nuclei. J Comp Neurol 463:13–24 reported by several studies (Gobel et al. 1981; Rene- 2. Beggs J, Jordan S, Ericson AC et al. (2003) Synaptology of han et al. 1986). In cats, laminae I, outer II and V (the Trigemino- and Spinothalamic Lamina I Terminations in the Pos- terior Ventral Medial Nucleus of the Macaque. J Comp Neurol lateral parts of medullary reticular formation) receive 459:334–354 inputs from small A-delta fibers and c-fibers, which 3. Gobel S, Hockfield S, Ruda MA (1981) An Anatomical Analysis convey information about pain or thermal sensation. of the Similarities between Medullary and Spinal Dorsal Horns. In contrast, low-threshold mechanoreceptive afferents In: Kawamura Y and Dubner R (eds) Oral-Facial Sensory and Motor Functions. Quintessence, Tokyo, pp 211–223 (A-beta) terminate throughoutinner lamina II to lamina 4. Hayashi H (1985) Morphology of Terminations of Small and V. However, rat laminae III/IV also receive input from Large Myelinated Trigeminal Primary Afferent Fibers in the Cat. nociceptive primary afferents (Jacquin et al. 1988). J Comp Neurol 240:71–89 Pulpal afferent boutons in the superficial layers in rats 5. Jacquin MF, Stennett RA, Renehan WE et al. (1988) Structure- Function Relationships in the Rat Brainstem Subnucleus Interpo- can be classified into those with clear, round (S-type) laris: II. Low and High Threshold Trigeminal Primary Afferents. vesicles and dense-cored vesicles, in contrast to pulpal J Comp Neurol 267:107–130 boutons in the rostral nuclei (Bae et al. 2003). Un- 6. Marfurt CF, Turner DF (1984) The Central Projections of Tooth Pulp Afferent Neurons in the Rat as Demonstrated by the Trans- myelinated nociceptive primary afferents have been ganglionic Transport of Horseradish Peroxidase. J Comp Neurol found to bear terminal varicosities that contain a large 223:535–547 number of dense-cored vesicles as well as clear, round 7. Nasution ID, Shigenaga Y (1987) Ascending and Descending vesicles (Bae et al. 2003). In addition, the occurrence of Internuclear Projections within the Trigeminal Sensory Nuclear Complex. Brain Res 425:234–247 synaptic glomeruli and of axoaxonic contacts is much 8. Olszewski J (1950) On the Anatomical and Functional Or- less frequent in the Vc than in the Vp. ganization of the Spinal Trigeminal Nucleus. J Comp Neurol The projection patterns of primary afferents in the Vc 92:402–413 have also been examined in cats using the technique 9. Renehan WE, Jacquin MF, Mooney RD, Rhoades RW (1986) Structure-Function Relationships in Rat Medullary and Cervical of transganglionic transport of HRP (Shigenaga et al. Dorsal Horns. II. Medullary Dorsal Horn Cells. J Neurophysiol 1986a; Shigenaga et al. 1988; Shigenaga et al. 1989b). 55:1187–1201 All three trigeminal divisions terminate throughout 10. Shigenaga Y, Chen IC, Suemune S et al. (1986a) Oral and Facial laminae I-V,with the exception of tooth pulp, jaw mus- Representation within the Medullary and Upper Cervical Dorsal Horns in the Cat. J Comp Neurol 243:388–408 cle and corneal afferents, which terminate in laminae 11. Shigenaga Y, Doe K, Suemune S et al. (1989a) Physiological I, outer II, and V. However, the mediolateral arrange- and Morphological Characteristics of Periodontal Mesencephalic mentsand caudalextensionsdiffer betweenthe different Trigeminal Neurons – Intra-Axonal Staining with HRP.Brain Res nerves or branches. 505:91–110 12. Shigenaga Y, Nakatani Z, Nishimori T et al. (1983) The Cells Theintraoralandfacialstructuresarearrangedasaseries of Origin of Cat Trigeminothalamic Projections: Especially in of concentric semicircular ringsthatare centeredaround the Caudal Medulla. Brain Res 277:201–222 the midline of the most anterior face and mouth, and are 13. Shigenaga Y, Nishimura M, Suemune S et al. (1989b) Somato- topic Organization of Tooth Pulp Primary Afferent Neurons in represented, especially in laminae I/II, in a consecutive the Cat. Brain Res 477:66–89 order. In this way, the midline of the mouth and the most 14. Shigenaga Y, Okamoto T, Nishimori T et al. (1986b) Oral and anterior face are represented most rostrally, while more Facial Representation in the Trigeminal Principal and Rostral lateral or posterior structures are represented at succes- Spinal Nuclei of the Cat. J Comp Neurol 244:1–18 15. Shigenaga Y, Sera M, Nishimori T et al. (1988) The Central Pro- sively more caudallevelsinthemedullaryanduppercer- jection of Masticatory Afferent Fibers to the Trigeminal Sensory vical dorsal horns (Fig. 2). The fact that neurons in lam- Nuclear Complex and Upper Cervical Spinal Cord. J Comp Neu- inae I, outer II and V receive inputs from nociceptive rol 268:489–507 or thermoreceptive afferents, and that lamina I neurons 16. Shigenaga Y,Suemune S, Nishimura T et al. (1986c) Topographic Representation of Lower and Upper Teeth Within the Trigemi- projectto the VPM (Shigenaga etal. 1983),Sm (Yoshida nal Sensory Nuclei od Adult Cat as Demonstrated by the Trans- et al. 1991) and in monkey, the posterior ventral medial ganglionic Transport of Horseradish Peroxidase. J Comp Neurol nucleus(VMpo)(Beggsetal. 2003),supporttheconcept 251:299–316 that the onionskin-like organization of pain and thermal 17. Tsuru K, Otani K, Kajiyama K et al. (1989) Central Terminations of Periodontal Mechanoreceptive and Tooth Pulp Afferents in sensations is defined by the arrangement of the sensory the Trigeminal Principal and Oral Nuclei of the Cat. Brain Res projections to lamina I and outer lamina II. An anatom- 485:29–61 Trigeminal Brainstem Nuclear Complex, Immunohistochemistry and Neurochemistry 2541

18. Westrum LE, Canfield RC, O’Conner TA (1981) Each Canine often referred to asthe medullarydorsalhornsinceitdis- Tooth Projects to all Brain Stem Trigeminal Nuclei in Cat. Exp plays several features, such as a laminated organization, Neurol 74:787–799 19. Yoshida A, Dostrovsky JO, Sessle BJ et al. (1991) Trigeminal similar to the spinal dorsal horn. Projections to the Nucleus Submedius of the Thalamus in the Rat. J Comp Neurol 307:609–625 Characteristics 20. Yoshida A, Hiraga T, Moritani Met al. (1998) Morphologic Char- The role of the different subnuclei of the TBNC in me- acteristics of Physiologically Defined Neurons in the Cat Trigem- inal Nucleus Principalis. J Comp Neurol 401:308–328 diating the various aspects of pain remains controver- 21. Yoshida A, Yasuda K, Dostrovsky JO et al. (1994) Two Major sial, since injurious stimuli can excite neurons through- Types of Premotoneurons in the Feline Trigeminal Nucleus Oralis out the TBNC (Sessle 2000), and orofacial tissues are as Demonstrated by Intracellular Staining with Horseradish Per- represented somatotopically at multiple, but intercon- oxidase. J Comp Neurol 347:495–514 nected, levels of the TBNC (Bereiter et al. 2000). The neurochemical organization of the TBNC has shed ad- ditional light on possible contributions of different por- tions of the TBNC to pain processing. Trigeminal Brainstem Nuclear Complex, Immunohistochemical approaches have identified two Immunohistochemistry and broad classes of small-diameter myelinated or unmyeli- Neurochemistry nated nerve fibers: i) fibers stained positive for the neu- ropeptides substance P, calcitonin gene-related peptide DAV I D A. BEREITER and  neurotrophins and ii) fibers stained positive for Department of Surgery, Brown Medical School, the cell-surface marker,  isolectin B4, and negative for Providence, RI, USA neuropeptides. As summarized in Table 1, both classes of small-diameter fibers terminate densely in laminae I- Definition II of Vc and the paratrigeminal islands and weaker, but The trigeminal brainstem nuclear complex (TBNC) is significant, labeling in deep laminae of Vc and dorso- comprised of the principal or main sensory nucleus and medial portions of rostral regions of the TBNC (Sugi- spinal trigeminal nucleus. moto et al. 1997a; Sugimoto et al. 1997b). Immunoreac- Thespinaltrigeminalnucleusisfurthersubdivided,from tivity for NK1, the substance P receptor, and TrkA, the rostralto caudal, into subnucleusoralis(Vo),subnucleus highaffinity-receptorfornervegrowthfactor,areconsis- interpolaris (Vi) and subnucleus caudalis (Vc), which is tent generally with the distribution of substance P- and nerve growth factor-positive fibers, respectively, within the TBNC (Krol et al. 2001; Nakaya et al. 1994). Markers associated with opioid analgesia such the  endogenous opioid peptide, endomorphin 2 (Martin- Schild et al. 1999), and the mu opioid receptor subtype, MOR1 (Ding et al. 1996), display moderate to dense immunoreactivity in laminae I-II of Vc, paratrigeminal islands and at the Vi/Vc transition region, while deeper T laminae of Vc and more rostral regions of the TBNC display weak or no staining.Physiologicalstudiesreveal that cornea-responsive neurons at the Vi/Vc transition region, i.e., the most rostral pole of Vc, are often en- hanced by increasing doses of morphine, suggesting a role for this region in recruitment of endogenous pain controls (Hirata et al. 2000). Receptors for monoamine transmitters (catecholamines and serotonin) display diffuse staining throughout most rostral regions of the TBNC; however, the superfi- cial laminae of Vc display moderate to dense levels of immunoreactivity (Day et al. 1997; Wright et al. 1995). Staining for choline acetyltransferase (ChAT), the biosynthesis enzyme for acetylcholine, is weak in Trigeminal Brainstem Nuclear Complex, Immunohistochemistry and Neurochemistry, Figure 1 Trigeminal brainstem nuclear complex of the most rostral regions of TBNC, while the superficial rat. Abbreviations: I-II, laminae I-II; III-V, laminae III-V; m, trigeminal motor laminae of Vc display moderate levels, consistent with n.; nts, n. tractus solitarii; Pa5, paratrigeminal islands; Vc, subnucleus the distribution of nicotinic receptors(Wadaetal. 1989). caudalis; Vi, subnucleus interpolaris; Vi/Vc, interpolaris/caudalis transition region; Vo, subnucleus oralis; Vp, principal sensory nucleus; Vtr, spinal Neurons that contain the inhibitory amino acid trans- trigeminal tract. Numbers below each outline indicate approximate distance mitter, GABA, are found in all regions of the TBNC, in mm caudal to bregma, a skull surface landmark. with the highest density in laminae I-II of Vc (Ginestal 2542 Trigeminal Brainstem Nuclear Complex, Immunohistochemistry and Neurochemistry

Trigeminal Brainstem Nuclear Complex, Immunohistochemistry and Neurochemistry, Table 1 Summary of the distribution of immunohistochemical markers associated with nociceptive processing in different portions of the trigeminal brainstem nuclear complex Vp Vo Vi Vi/Vc Pa5 Vc dm vl dm vl I-II III-V

IB4+-+-+-+++++-

SP+-+- +++++++++

CGRP++- ++-+ ++++++++

TrkA+-+- ++++++-

ChAT+-+- ++- +++

NR1+++++++++++++++++++

GABA+++++++++++++++

AR α/β +- +- ++++++

5HT1/2 +- +- ++++++ Endo2 + - + - + + ++ +++ -

MOR1-----++++++-

EP3------++++-

P2X2 +++++++++++ ER α ------+++-

Symbols and abbreviations:- = very weak or no staining; +,++,+++ = weak, moderate and dense staining; AR α/β, adrenergic receptor subtypes; CGRP, calcitonin gene-related peptide; ChAT, choline acetyltransferase; dm, dorsomedial; Endo2, endomorphin 2; EP3, prostaglandin receptor; ER α, estrogen receptor alpha subtype; GABA, gamma aminobutyric acid; 5HT1/2, serotonin receptor subtypes; IB4, isolectin B4; MOR1, mu opioid receptor; NR1, NMDA receptor subunit; P2X2, ATP receptor; Pa5, paratrigeminal islands; SP, substance P; TrkA, tyrosine kinase A receptor subtype; Vc, subnucleus caudalis; Vi, subnucleus interpolaris; Vi/Vc, interpolaris/caudalis transition region; Vo, subnucleus oralis; Vp, principal sensory nucleus; vl, ventrolateral and Matute 1993) in agreement with the distribution of input from small-diameter nerve fibers, the appearance subunits for the GABAA receptor (Fritschy and Mohler of selected markers for nociceptors and neuroplasticity 1995). in the dorsomedial portions of the principal sensory nu- Immunoreactivity for EP3, a subtype of the prostaglan- cleus and Vo, suggest that these regions also contribute din receptor, and well associated with inflammatory to the integration of specific forms of trigeminal pain. pain, occurs only in laminae I-II of Vc and the para- trigeminal islands (Nakamura et al. 2000). By contrast, References the purinergic receptor, P2X2, an ATP-gated ion chan- 1. Bereiter DA, Cioffi IL, Bereiter DF (2005) Oestrogen receptor- nel, (Kanjhan et al. 1999) and NR1, a subunit of the immunoreactive neurons in the trigeminal sensory system of male and cycling female rats. Arch Oral Biol 50:971–9 NMDA receptor (Petralia et al. 1994), receptors that are 2. Bereiter DA, Hirata H, Hu JW (2000) Trigeminal Subnucleus upregulated during inflammation and associated with Caudalis: Beyond Homologies with the Spinal Dorsal Horn. Pain  neuroplasticity, are widely distributed throughout 88:221–224 3. Day HE, Campeau S, Watson SJ, Akil H (1997) Distribution of the TBNC, although they have a higher density in Vc. α1a, α1b, and α1d-Adrenergic Receptor mRNA in the Rat Brain Several orofacial pain conditions (e.g., migraine and Spinal Cord. J Chem Neuroanat 13:115–139 headache, temporomandibular disorders) display a 4. Ding Y-Q, Kaneko T, Nomura S, Mizuno N (1996) Immunohis- significant sex-related prevalence. The basis for these tochemical Localization of μ-opioid Receptors in the Central Nervous System of the Rat. J Comp Neurol 367:375–402 sex differences is not certain. However, the distribution 5. Fritschy J-M, Mohler H (1995) GABAA-Receptor Heterogeneity of ERα, a major subtype of estrogen receptor, occurs in the Adult Rat Brain: Differential Regional and Cellular Dis- mainly in lamina II of Vc and not in more rostral regions tribution of Seven Major Subunits. J Comp Neurol 359:154–194 of the TBNC (Bereiter et al. 2005). 6. Ginestal E, Matute C (1993) Gamma-Aminobutyric Acid- Immunoreactive Neurons in the Rat Trigeminal Nuclei. Histo- The neurochemical organization of the TBNC is con- chemistry 99:49–55 sistent with the notion that, laminae I-II of Vc and the 7. Hirata H, Takeshita S, Hu JW, Bereiter DA (2000) Cornea– paratrigeminal islands receive direct input from small- Responsive Medullary Dorsal Horn Neurons: Modulation diameter nerve fibers, and play an essential role in the by Local Opioid Agonists and Projections to Thalamus and Brainstem. J Neurophysiol 84:1050–1061 processing and modulation of trigeminalpain. Although 8. Kanjhan R, Housley GD, Burton LD, Christie DL, Kippenberger rostral regions of the TNBC receive only sparse direct A, Thorne PR, L.Luo, Ryan AF (1999) Distribution of the P2X2 Trigeminal Brainstem Nuclear Complex, Physiology 2543

Receptor Subunit of the ATP-gated Ion Channels in the Rat Cen- important features that have prompted the study of V tral Nervous System. J Comp Neurol 407:11–32 nociception, and may be manifested clinically in the 9. Krol KM, Stein EJ, Elliot J, Kawaja MD (2001) TrkA-Expressing Trigeminal Sensory Neurons Display both Neurochemical and unique trigeminal pain conditions, such as toothache, Structural Plasticity Despite a Loss of p75 NTR Function: Re- migraine, V neuralgia, temporomandibular disorders sponses to Normal and Elevated Levels of Nerve Growth Factor. and other idiopathic orofacial pains. Eur J Neurosci 13:35–47 10. Martin-Schild S, Gerall AA, Kastin AJ, Zadina JE (1999) Dif- Characteristics ferential Distribution of Endomorphin 1-and Endomorphin2-like Immunoreactivies in the CNS of the Rodent. J Comp Neurol Trigeminal Brainstem Nuclear Complex (VBNC) Organization 405:450–471 11. Nakamura K, Kaneko T, Yamashita Y, Hasegawa H, Katoh Most V primary afferents have their cell bodies in the H, Negishi M (2000) Immunohistochemical Localization of V ganglion and project centrally to the VBNC, where Prostaglandin EP3 Receptor in the Rat Nervous System. J Comp they ascend to the main (or principal, Vp) sensory nu- Neurol 421:543–569 cleus and/or descend to the spinal tract nucleus, which 12. Nakaya Y, Kaneko T, Shigemoto R, Nakanishi S, Mizuno N (1994) Immunohistochemical Localization of Substance P Re- includes subnuclei oralis (Vo),interpolaris (Vi) and cau- ceptor in the Central Nervous System of the Adult Rat. J Comp dalis (Vc); see essay by Shigenaga and Yoshida (Fig. 1). Neurol 347:249–274 The most caudal, Vc, is a laminated structure that ex- 13. Petralia RS, Yokotani N, Wenthold RJ (1994) Light and Electron tends caudally into the dorsal horn of the cervical spinal Microscope Distribution of the NMDA Receptor Subunit NM- DAR1 in the Rat Nervous System using a Selective Anti-Peptide cord with which it is homologous. For this reason, it is Antibody. J Neurosci 14:667–696 also called themedullary dorsalhorn (Gobeletal. 1981). 14. Sessle BJ (2000) Acute and Chronic Craniofacial Pain: Brainstem Almost all nociceptive  CFiber afferents from the V Mechanisms of Nociceptive Transmission and Neuroplasticity, and their Clinical Correlates. Crit Rev Oral Biol Med 11:57–91 nerve have their central terminals distributed in the Vc 15. Sugimoto T, Fujiyoshi Y, He Y-F, Xiao C, Ichikawa H (1997a) and Vi/Vc transition zone. Terminals of the A-δ fiber Trigeminal Primary Projection to the Rat Brain Stem Sen- afferents are also found in Vc; however some, mostly sory Trigeminal Nuclear Complex and Surrounding Structures from the oral and perioral area, are found rostral to Vc; Revealed by Anterograde Transport of Cholera Toxin B δ Subunit-Conjugated and Bandeiraea Simplicifolia Isolectin B4- in particular, A- fibers from the dental pulp have been Conjugated Horseradish Peroxidase. Neurosci Res 28:361–371 described to be in the rostral divisions, Vp, Vo, Vi, (see 16. Sugimoto T, Fujiyoshi Y, Xiao C, He Y-F, Ichikawa H (1997b) essay by Shigenaga and Yoshida). The somatotopic or- Central Projection of Calcitonin Gene-Related Peptide (CGRP)- ganization of VBNC is also described in the essay by and Substance P (SP)-Immunoreactive Trigeminal Primary Neu- rons in the Rat. J Comp Neurol 378:425–442 Shigenaga and Yoshida. 17. Wada E, Wada K, Boulter J, Deneris E, Heinemann S, Patrick J, Swanson LW (1989) Distribution of alpha2, alpha3, aplha4, General Features of Nociceptive Processing in Subnucleus and beta2 Neuronal Nicotinic Receptor Subunit mRNAs in the Caudalis Central Nervous System: A Hybridization Histochemical Study  in the Rat. J Comp Neurol 284:314–335 In 1938, Sjöqvist reported that trigeminal tractotomy, 18. Wright DE, Seroogy KB, Lundgren KH, Davis BM, Jennes which interrupts the inputs to the Vc by severing the L (1995) Comparative Localization of Serotonin 1A, 1C and V spinal tract at the upper level of Vc, was an efficient 2 Receptor Subtype mRNAs in Rat Brain. J Comp Neurol treatment for  trigeminal neuralgia. The effect of 351:357–373 Vc deafferentation by tractotomy has repeatedly been T confirmed by neurosurgeons and animal researchers, and it has therefore long been considered that Vc is Trigeminal Brainstem Nuclear Complex, the crucial brainstem center for orofacial nociceptive Physiology processing. However, this procedure has little effect on tactile sensation and intraoral pain. These results 1 2 JAMES W. HU ,ALAIN WODA indicate the involvement of the rostral nuclei, such as 1Faculty of Dentistry, University of Toronto, Toronto, the Vo, in toothache or other pain sensations from the ON, Canada oral area (Young 1982). Thus neurons in V0,aswellas 2Faculté de Chirurgie Dentaire, University Clermont- Vc, are involved in ascending pathways contributing to Ferrand, Clermont-Ferrand, France orofacial pain (also see below). In the case of autonomic [email protected], [email protected] responses to noxious stimuli, such as cardiovascular and secretory reflexes (e.g. lacrimation and salivation), Definition the trigeminal brainstem regions that mediate these evoked responses include the Vi/Vc transition zone and Trigeminal (V) Brainstem Nuclear Complex (VBNC, medial regions of the VBNC that border the reticular Fig. 1) is the site of the first synapse of most V sen- formation. sory primary afferents and of considerable sensory The fact that Vc is critical for V nociception is supported processing and modulation. Its anatomy and physiol- by 7 pieces of evidence: ogy, although generally similar to the spinal sensory system, display several differences. These differences, 1. Vc receives A-δ and C nociceptive afferents that ter- and the existence of specialized organs and tissues, are minate in laminae I and II 2544 Trigeminal Brainstem Nuclear Complex, Physiology

Trigeminal Brainstem Nuclear Complex, Physiology, Figure 1 Schema of nociceptive somatosensory organisation of the orofacial area. The trigeminal nerve is made up of three divisions, ophthalmic (V1), maxillary (V2) and mandibular (V3), which supply a wide variety of tissues; note that V2 and V3 as well as V1 also supply part of the meninges. The primary afferent neurons mediating nociceptive messages (A-delta and C) project to the spinal tract nucleus. Ascending pathways arise from spinal tract nucleus to reach suprasegmental levels such as the thalamus and cerebral cortex. There are also important pathways descending from the suprasegmental centers to modulate the afferent messages, such as the cerebral cortex. Modified with permission from Dallel et al. 2003 Medecine/sciences 19: 567–574.

2. Vc is a laminated structure with a substantia gelati- Trigeminal Brainstem Nuclear Complex, Physiology, Table 1 Conv- nosa (lamina II) region, which is known to be asso- ergence of Nociceptive Afferent Inputs to Nociceptive Neurons in Trigeminal ciated with pain processing and a high concentration Subnucleus Caudalis of Cats of neuropeptide markers for nociception Facial Skin/Oral Mucosa 100%  3. Vc contains nociceptive neurons, either wide- Tooth pulp 66% dynamic-range (WDR) or nociceptive-specific (NS). These nociceptive neurons predominate in the lam- Muscle (jaw or tongue) 55% inae I, V and VI, and display positive stimulus- Temporomandibular joint (TMJ) 35% response functions to various afferent inputs, and can therefore code the intensity of different types of Laryngeal mucosa (Viscera) 55% noxious stimuli, including those arising from spe- Upper cervical nerves 50% cialized orofacial structures (Price et al. 1976; Sessle 2000). In addition, these Vc nociciceptive neurons Based upon a sample of approximately 100 WDR and NS neurons with also receive a wide range of inputs (see Table 1) cutaneous or intraoral mechanoreceptive fields; from Sessle et al. 1986 4. Some Vc nociceptive neurons send their axons into ascending nociceptive pathways that reach the thala- rons correlate well with the clinical observation of mus (Price et al. 1976) allodynia and hyperalgesia associated with inflam- 5. Some Vc neurons serve as reflex interneurons in re- matory (Chiang et al. 1998) or nerve injury-induced flexresponsestonoxiousorofacialstimuli(seeSessle neuropathic (Iwata et al. 2001) pain conditions. 2000) 6. Vc nociceptive neurons are subject to several affer- ent and descending antinociceptive modulatory in- Special Features of Trigeminal Brainstem Nociceptive Pro- fluences, as well as pharmacological antinociceptive cessing modulations (Sessle 2000; Ren and Dubner 2002) 1. Nociceptive processing in VBNC is not restricted to 7. In certain conditions (e.g. inflammation or nerve Vc: Nociceptive neurons activated from the orofacial injury), these nociceptive neurons manifest some area are also observed rostrally in Vo and Vi (Dallel et neuroplastic changes, such as increase in sponta- al. 1990; Sessle 2000). Vo convergent neurons share all neous activity, reduction of activation threshold, the properties of other neurons of the deep spinal dorsal increase response magnitude to noxious stimuli and horn, or of deep layersof Vc, (Dallel etal. 1990; Hu etal. receptive field expansion (Hu et al. 1992). Induction 1992) including plasticity (Sessle 2000). These neurons of these neuroplastic changes is an NMDA receptor- may play a role in reflex responses to noxious orofacial dependent process (Chiang et al. 1998) (Fig. 2). stimulation (see Shigenaga and Yoshida essay), but These neuroplastic changes in the nociceptive neu- results of V tractotomy (see above) indicate that oral Trigeminal Brainstem Nuclear Complex, Physiology 2545

Trigeminal Brainstem Nuclear Complex, Physiology, Figure 2 Rat caudalis nociceptive-specific (NS) neuron showing neuroplastic changes in neuronal properties after small-fiber excitant, and inflammatory irritant mustard oil (MO) application to the maxillary right molar pulp. In (a), histologically retrieved recording site and the arrow indicates the neuronal recording site in caudalis and in (b), mechanoreceptive field (RF) sizes before (0 min.) and 10 min. after MO application (i.e. solid area represents pinch RF and ‘Red’ area, with a thin red arrow, represents a newly defined tactile RF that also responded to pinch stimulus after MO application). In (b), blackened area indicates the RF location and size, which only noxious pinch stimulation activated, before MO application. The RF expansion 10 minutes after MO application and a small stripped area that appeared only after the application of MO, indicated by a thin arrow, that a brush (low-threshold mechanical) stimulus can also activate this NS neuron that previously was unable to respond to this brush stimulus. In (c), MO-induced a brief burst of discharges followed by higher firing rate than the baseline level (0 min). This response represents an input from the maxillary tooth pulp. In (d), neuronal responses to mechanical and thermal stimuli applied to the cutaneous RF. Top trace: marker of brush (Br), pressure (Pr), pinch (Pi) and radiant heat (RH). Middle trace: neuronal responses in control conditions (i.e. Pre-MO before MO application). Bottom trace: neuronal responses to same stimuli 20 min after MO application (i.e. Post-MO after MO application). In (e), neuronal responses to graded mechanical stimuli (50, 100, and 200 g). Each stimulus lasts for 3 s, and the y-axis scale (omitted) is the same for middle and bottom traces in a and b. Binwidth is 1 s. Note that after MO application this NS neuron became responsive to light brushing (thin arrow) and radiant heating (thick arrow) of the cutaneous RF, and strongly responsive to graded pinch stimuli. Modified with permission from Chiang et al. (1998). T and perioral pain sensation also depends on Vo. Another in nociceptive neurons of Vo can be modulated, either indication of a sensory role for Vo as well as Vc is the facilitated or inhibited, by neurochemicals injected into presence of a similar density of anatomical projections the Vc substantia gelatinosa (Dallel et al. 1998; Woda from these two subnuclei to higher levels of the brain. et al. 2001; Hu et al. 2002). In addition, nociceptive thalamic neurons can still be 2. Some specialized orofacial tissues receive innerva- recorded after stimulation of oral and perioral areas, in tion patterns unique to the trigeminal system. Unlike the spite of the deafferentation of Vc by trigeminal tracto- skin, specialized V structures, such as the tooth pulp, tomy (Raboisson et al. 1989). In Vo,the C-fiber primary meninges and cornea are innervated mainly by A-δ and afferent endings are scarce and a substantia gelatinosa C nociceptive afferents, since very few or no A-β affer- is lacking. However, C-fiber evoked activities recorded ents can be found. Single unit-recording studies have in Vo relay in the substantia gelatinosa of Vc (Dallel et shown that the VBNC nociceptive neurons activated al. 1998). The influence on the properties of Voneurons from these specialized tissues often receive convergent of the substantia gelatinosa of Vc constitutes a unique inputs from a wide range of structures including facial feature, which can be used as an experimental model skin. The distribution of V neurons that encode nocicep- (Fig. 3), since it offers the possibility of recording from tive information from these specialized orofacial tissues deep layer nociceptive neurons, i.e. in Vo, while in- display a complex pattern, which is characterized by jecting neurochemicals in the Vc substantia gelatinosa. their occurrence at different rostrocaudal levels of the Indeed, it has been shown that plastic changes observed VBNC. 2546 Trigeminal Ganglion

6. Hoffman DS, Dubner R, Hayes RL, Medlin TP (1981) Neuronal Activity in Medullary Dorsal Horn of Awake Monkeys Trained in a Thermal Discrimination Task. I. Responses to Innocuous and Noxious Thermal Stimuli. J Neurophysiol 46:409–427 7. Hu B, Chiang CY, Hu JW, Dostrovsky JO, Sessle BJ (2002) P2X Receptors in Trigeminal Subnucleus Caudalis Modulate Central Sensitization in Trigeminal Subnucleus Oralis. J Neurophysiol 88:1614–1624 8. Hu JW, Sessle BJ, Raboisson P, Dallel R, Woda A (1992). Stimu- lation of Craniofacial Muscle Afferents Induces Prolonged Facil- itatory Effects in Trigeminal Nociceptive Brain-Stem Neurones. Pain 48:53–60 9. Iwata K, Imai T, Tsuboi Y, Tashiro A, Ogawa A, Morimoto T, Masuda Y,Tachibana Y,Hu J (2001) Alteration of Medullary Dor- sal Horn Neuronal Activity Following Inferior Alveolar Nerve Transection in Rats. J Neurophysiol 86:2868–2877 10. Price DD, Dubner R, Hu JW (1976) Trigeminothalamic Neu- rons in Nucleus Caudalis Responsive to Tactile, Thermal, and Nociceptive Stimulation of Monkey’s Face. J Neurophysiol 39:936–953 11. Raboisson P, Dallel R, Woda A (1989) Responses of Neurones in the Ventrobasal Complex of the Thalamus to Orofacial Noxious Stimulation after Large Trigeminal Tractotomy. Exp Brain Res 77:569–576 12. Ren K, Dubner R (2002) Descending Modulation in Persistent Pain: An Update. Pain 100:1–6 Trigeminal BrainstemNuclear Complex, Physiology, Figure 3 Schem- 13. Sessle BJ (2000) Acute and Chronic Craniofacial Pain: Brainstem atic dorsal view of the spinal tract nucleus of VBNC that illustrates the sub- Mechanisms of Nociceptive Transmission and Neuroplasticity, nucleus oralis-subnucleus caudalis experimental model. The subnucleus and their Clinical Correlates. Crit Rev Oral Biol Med 11:57–91 oralis is activated only indirectly by primary afferent C-fibers. A relay in the 14. Woda A, Molat JL, Luccarini P (2001) Low Doses of N-methyl- substantia gelatinosa in subnucleus caudalis is mandatory, since there is no D-aspartate Antagonists in Superficial Laminae of Medulla direct C fiber projection to Vo. This allows for recordings from nociceptive Oblongata Facilitate Wind-Up of Convergent Neurones. Neu- neurons while injecting chemicals into the substantia gelatinosa. roscience 107:317–327 15. Young RF (1982) Effect of Trigeminal Tractotomy on Dental Sensation in Humans. J Neurosurg 56:812–818 3. The VBNC also offers the possibility of extending the knowledge base relevant to spinal neuronal proper- ties from anaesthetized to awake conditions. Taking ad- Trigeminal Ganglion vantage of the unique location of the medullary dorsal horn (Vc), Dubner and his colleagues recorded Vc sin- Definition gle neurons in conscious monkeys while performing be- havioral tasks relevant to nociception (Hoffman et al. A nerve ganglion where the cell bodies of the afferent 1981). While the properties of WDR and NS neurons in neurones innervating the orofacial area are located. Vc observed in anaesthetized animals during recordings  Nociceptors in the Dental Pulp were confirmed in the conscious monkeys, these experi- ments also showed that many of these Vc neurons could be modulated through attentional and motivational fac- Trigeminal Lemniscus tors. Definition References 1. Bereiter DA, Hirata H, Hu JW (2000) Trigeminal Subnucleus Trigeminalcutaneousprojectiontothethalamus,incon- Caudalis: Beyond Homologies with the Spinal Dorsal Horn. Pain trast to the spinal lemniscus. 88:221–224  Parafascicular Nucleus, Pain Modulation 2. Chiang CY, Park SJ, Kwan CL, Hu JW, Sessle BJ (1998) NMDA Receptor Mechanisms Contribute to the Trigeminal Nociceptive Neuronal Plasticity Induced by Mustard Oil Application to the Rat Molar Tooth Pulp. J Neurophysiol 80.2621–2631 3. DallelD, DualeC, Molat JL (1998)Morphine Administered in the Trigeminal Motor Nucleus Substantia Gelatinosa of the Spinal Trigeminal Nucleus Caudalis Inhibits Nociceptive Activities in the Spinal Trigeminal Nucleus Definition Oralis. J Neurosci 18:3529–3536 4. Dallel R, Raboisson P, Woda A, Sessle BJ (1990). Properties of Also called masticatory nucleus, it is located in the dor- Nociceptive and Non-Nociceptive Neurons in Trigeminal Sub- sal mid-pons, close to the trigeminal principal sensory nucleus Oralis of the Rat. Brain Res 521:95–106 nucleus, and contains motoneurons for both jaw-closing 5. Gobel S, Hockfield S, Ruda MA (1981) Anatomical Similari- and jaw-opening muscles. ties between Medullary and Spinal Dorsal Horns. In: Kawamura  Y, Dubner R (eds) Oral-Facial Sensory and Motor Functions. Jaw-Muscle Silent Periods (Exteroceptive Suppres- Quintessence Publishing Co, Tokyo, Berlin, pp 211–223 sion) Trigeminal Neuralgia, Diagnosis and Treatment 2547

 Trigeminal Neuralgia, Etiology, Pathogenesis and Trigeminal Nerve Management Definition The trigeminal nerve is the largest cranial nerve and in- Trigeminal Neuralgia, Diagnosis and nervatesmuchofthecutaneouscraniofacialregions.The Treatment trigeminal nerve also innervates the muscles of mastica- tion. The three major divisions of the trigeminal nerve DONALD R. NIXDORF are ophthalmic, maxillary and mandibular nerves. An Department of Diagnostic and Biological Sciences, extremely painful condition, tic douloureux, occurs in School of Dentistry, University of Minnesota, the territory of the trigeminal nerve and likely involves Minneapolis, MN, USA primary afferent fibers of the trigeminal nerve. [email protected]  Amygdala, Pain Processing and Behavior in Animals  Nociception in Nose and Oral Mucosa Synonyms  Trigeminothalamic Tract Projections Tic douloureux Definition Trigeminal Neuralgia Trigeminal neuralgia is an excruciating pain felt in the distribution of the trigeminal or fifth cranial nerve and is Synonyms classically described as a brief sharp shooting pain (Kitt Tic douloureux et al. 2000). Trigeminal neuralgia has been defined by the International Headache Society’s classification sub- Definition committee as (IHS 2004): Trigeminal neuralgia is an idiopathic, episodic severe  pain condition of the orofacial region often described as A) Paroxysmal attacks of pain lasting from a fraction electric-shock-like sensations that can be triggered by of a second to 2 minutes, affecting one or more divi- innocuousstimuli, associated with injury or dysfunction sions of the trigeminal nerve and fulfilling criteria B of the fifth cranial nerve (trigeminal nerve) or its gan- and C. glion and felt in the distribution of this nerve. It is con- B) Pain has at least one of the following characteristics: sidered as a prototype of neuropathic pain. Trigeminal 1. intense, sharp, superficial or stabbing neuralgia (tic douloureux) may have no apparent cause 2. precipitated from trigger areasor bytriggerfactors or be associated with neurovascular conflictbetween the trigeminal root and an anomalous vascular loop (classi- cal trigeminal neuralgia), or be secondary to benign tu- C) Attacks are stereotyped in the individual patient mors of the cerebellopontine angle or multiple sclerosis. D) There is no clinically evident neurological deficit  Central Pain in Multiple Sclerosis E) Not attributed to another disorder  Demyelination Although this definition has never been tested for reli- T  Jaw-Muscle Silent Periods (Exteroceptive Suppres- ability and proven to be valid, either it, or a derivation, sion) are widely accepted and utilized extensively for both re-  Neuralgia, Assessment search and patient care purposes.  Neuralgia, Diagnosis Note: the terms classical trigeminal neuralgia and idio-  Pain Paroxysms pathic trigeminal neuralgia are used when a secondary  Paroxysmal Hemicrania cause for this pain is not readily identifiable. Symp-  Primary Stabbing Headache tomatic trigeminal neuralgia is used when a secondary  Tic and Cranial Neuralgias cause for this pain has been identified, such as an  Trigeminal Brainstem Nuclear Complex, Physiology aneurysm, tumor or stroke.  Trigeminal Neuralgia, Etiology, Pathogenesis and Management Characteristics Trigeminal neuralgia occurs in approximately 4 per 100,000 people and has an onset later in life, with the Trigeminal Neuralgia, Aims of Surgical median age of diagnosis being 67 years old. It occurs Management about twice as often in women as in men (Katusic et al. 1990), but this may be from sampling error, since good Definition prevalence data do not exist (Zakrzewska and Hamlyn Surgical management of trigeminal neuralgia can pro- 1999). This severe pain is described by patients as hav- vide complete pain relief for periods ranging from ayear ing an electric or lightening bolt quality and being brief to 10 years. in duration, lasting less than 30 seconds. Sometimes 2548 Trigeminal Neuralgia, Diagnosis and Treatment patients describe a dull, burning or throbbing pain that Etiology and Pathophysiology occurs between attacks of intense pain. Trigeminal The etiology of trigeminal neuralgia is not established neuralgia pain is most commonly felt in the maxillary and little is truly understood about the underlying pain division and to alesser extentin themandibulardivision. mechanisms, since a valid animal model does not exist. Pain is infrequently felt only in the ophthalmic division Trigeminal nerve root compression, at the entry zone of the trigeminal nerve. It is almost always unilateral, into the  pons, has been observed in patients with especially on initial presentation and does not cross the trigeminal neuralgia (Dandy 1934). The anatomical midline. There may be predilection for right-sided pain arrangement of blood vessel impingement on the nerve (Zakrzewska and Hamlyn 1999), which would suggest root has also been described in patients after surgical an anatomical correlation. Paroxysms of pain may be exploration (Jannetta 1967), but it is not present in all spontaneous, occurring without a known reason or patients with trigeminal neuralgia and sometimes it is triggered by non-painful stimuli such as light touch or noted in imaging of non-trigeminal neuralgia patients wind on the face, eating and grooming. The triggering (Majoie et al. 1997). It has been hypothesized that the area may be the area where the pain is felt or different, presence of  ectopic action potentials arising from but it is always on the same side as the pain and is often peripheral nerves and the failure of central inhibition perioral. Local anesthetic applied to the triggering area within the trigeminal system occur simultaneously to will abate the ability to trigger the pain. Once pain is produce paroxysmal pain. This explains why certain triggered it is self-sustaining and frequent triggering medications are beneficial and others are not in the often results in a decrease in pain intensity in the later treatment of trigeminal neuralgia (Fromm et al. 1984). bouts of pain. Interestingly, even though this pain is Currently, the phenomenon of ephaptic cross talk is one of the worst pains imaginable, it is not triggerable used to explain how non-painful stimuli are translated during unconsciousness and rarely wakes people from into painful ones and crossed  afterdischarge has been sleep. Also, trigeminal neuralgia is characterized as cited as the mechanism implicated in further pain am- having periods of spontaneous remission, which may plification and prolongation. These two assumptions last days, months or even years. have been collectively termed the ‘ignition hypothe- sis’, which defines trigeminal neuralgia as a peripheral Diagnostic Process nerve disorder (Devor et al. 2002). This hypothesis ex- The diagnosis of trigeminal neuralgia is based strictly plains why people with demyelinating disorders, such on clinical data, i.e. a history and physical examination, as multiple sclerosis, frequently experience trigeminal since there are no laboratory tests or imaging studies neuralgia. It may also account for the clinical observa- that can either confirm or refute its presence (Merskey tion that trigeminal neuralgia seems to start after recent and Bogduk 1994; IHS 2004). Brain imaging is fre- dental interventions. The continuous dull burning back- quently ordered to ensure that trigeminal neuralgia is ground pain sometimes felt by patients would best be not caused by an intracranial space-occupying lesion explained by the development of central sensitization or  demyelinating process. Trigeminal neuralgia is secondary to a lack of inhibition, akin to deafferentation 20 times more common in people with multiple scle- pain and other continuous neuropathic pains. rosis (Katusic et al. 1990), so when it occurs in young patients, the appropriate evaluative measures should be Treatment performed. Overview Patients sometimes present to their dentist first, because Whenever possible, treatment should be directed at this pain is frequently felt in the jaws and teeth. Often the etiological factors or tailored to the mechanisms their description is of a continuous dull ache, similar to involved. Since these are largely unknown, current toothache. There is controversy about this pain because treatments have developed from empiric practice. Data itmayactuallybeaprodrometotheclassicallydescribed exist regarding pharmacological and surgical treatment trigeminal neuralgia, occurring days to years before the options, but little or nothing is published about psy- more recognizable symptoms occur. This prodrome chological interventions. In my opinion, as with other pain has been termed pre-trigeminal neuralgia and cor- chronic pains, some trigeminal neuralgia patients may respondstotheinitialpresentationfeaturesoftrigeminal benefit from a cognitive behavioral approach to care that neuralgia. Thisconceptissupportedby patientreporting also includes stress reduction and coping strategies. The and by clinical experience that this prodrome pain re- following is a summation of the best available research sponds to pharmacotherapy like classic trigeminal neu- published. ralgia does (Fromm et al. 1990). The opposing opinion is that the continuous dull ache pain is really of odonto- Pharmacological Treatment Options genic origin. Dental interventions, like root canals and Pharmacotherapy, also known as medication or drug tooth extractions, employed to address pathology result therapy, is considered the first-line treatment for trigem- in peripheral nerve injury and this cumulative injury inal neuralgia (Kitt et al. 2000). Anticonvulsant medi- leads, in part, to the formation of trigeminal neuralgia. cations or drugs that have membrane-stabilizing prop- Trigeminal Neuralgia, Diagnosis and Treatment 2549 erties, meaning that they reduce spontaneous nerve ac- to carbamazepine, pain frequency was reduced with tivity, are typically used for the treatment of trigeminal dosages of up to 80 mg per day (Sindrup and Jensen neuralgia.Thesemedicationshavebeenshowninanimal 2002). experiments to suppress the response of mechanorecep- Newer anticonvulsant medications have shown some tors and augment presynaptic afferent inhibition within potential for successful future use based primarily on the maxillary nerve; this has been correlated with clin- their lower side effect profile, as well as on some limited ical drug efficacy (Fromm et al. 1981). Therefore, the research data. Lamotrigine hasbeen studiedin one small goal of pharmacotherapy is to augment inhibitory path- controlled trial as an add-on medication. Its mechanism ways and reduce ectopic and  ephaptic neuronal firing. of action has not been totally elucidated, but it has been Randomized placebo controlled trials for the treatment reported to block sodium channels and inhibit presy- of trigeminal neuralgia are rare. The low prevalence naptic glutamate release. At doses of 400 mg per day in the population and the occurrence of spontaneous it has been shown to reduce trigeminal neuralgia pain symptom remission make it difficult to study. (Zakrzewska et al. 1997). Topiramate has been studied Carbamazepine is an older anticonvulsant medication in a very small controlled trial as an add-on medication. that has been studied the most and clinically utilized The exact mechanisms of action are also not known, but often. Three randomized controlled studies have eval- it is thought to block sodium channels, inhibit glutamate uated carbamazepine for the treatment of trigeminal binding and act as a GABAA agonist. At doses of up neuralgia and have found that it reduces pain severity, to 600 mg per day, it reduced trigeminal neuralgia pain frequency and trigger sensitivity. Up to 75% of patients intensity, duration and frequency (Gilron et al. 2001). taking carbamazepine find it effective for long-term Gabapentin, which is thought to cause calcium channel pain reduction (Sindrup and Jensen 2002). Sodium blockade, has been reported to be helpful in case reports channel blockade is the accepted mechanism of action in dosages of up to 2700 mg per day (Sist et al. 1997). for carbamazepine; this results in a reduction of nerve Its side effect profile tends to be the most favorable of excitation and axonal firing. Dosing is by titration to all anticonvulsant medications but dizziness, fatigue, the clinical effect of pain reduction, initiating at 200 mg ataxia and weight gain can occur. Oxcarbazepine was a day, increasing at a maximum rate of 200 mg per day evaluated in a small, uncontrolled study of patients with to a maximum dosage of 1200 mg per day in divided refractory trigeminal neuralgia; patients reported pain doses. Most patients respond between 400–800 mg per reliefondosesaround1200mgperday(Zakrzewskaand day, which corresponds to serum levels between 20 and Patsalos 2002). Oxcarbazepine is chemically related 40 μmol/L (Sindrup and Jensen 2002). Side effects of to carbamazepine and also blocks sodium channels. It carbamazepine include hepatic induction and toxicity, is reported to have far fewer side effects and does not hematopoietic suppression, electrolyte imbalances, require monitoring with laboratory testing, but dose multiple drug interactions and cognitive impairment. dependent  hyponatremia has been reported. These side effects can be serious; therefore, laboratory Theutilityofothermedicationstypicallyusedinchronic monitoring to ensure early detection of potential prob- pain, such as tricyclic antidepressants and opioid anal- lems is required. Side effects are often very limiting for gesics for the treatment of trigeminal neuralgia has not patients and can cause them to discontinue use, even been systematically researched. Conceptually, most T when profound pain reduction is achieved. clinicians agree that these medications have a role in Phenytoin and valproic acid are two other older anticon- the management of trigeminal neuralgia when it is re- vulsant medications that have not been systematically fractory to previous treatment or when it has an atypical studied. Both phenytoin and valproic acid block sodium presentation, such as concurrent continuous pain. channels, while valproic acid also increases gamma- aminobutyric acid (GABA) and enhances glutamate Surgical Treatment Options decarboxylase. Case series information suggests that Surgical treatment is usually reserved for patients who doses of 300 mg per day of phenytoin and 1200 mg fail first line drug therapy due to uncontrollable pain or per day of valproic acid are effective for pain reduction intolerable side effects. The target for surgery is the pe- (Sindrup and Jensen 2002). Both drugs are becoming ripheral nerve, with either nerve ablation or decompres- used less often because they are hampered by similar sion the goal. There are no randomized controlled tri- side effects and monitoring issues as carbamazepine. als that investigate the effects of surgical treatment op- Also, clinical experience suggests that they do not tions; thus the advantages and disadvantages of the var- produce the same robust reduction in pain symptoms. ious procedures are based on personal opinion (Kitt et  Clonazepam, a GABAA agonist, and baclofen, a al. 2000). Historically, peripheral neurectomy was the GABAB agonist, are labeled as muscle relaxants and are preferred procedure for trigeminal neuralgia, using ei- beingusedforthetreatmentoftrigeminalneuralgia.One ther mechanical or chemical means. This procedure has small, uncontrolled trial suggested that clonazepam, at been replaced by other surgical options that result in re- doses of 6–8 mg per day, may be helpful. In a small duced sensory deficits and higher success. Dental treat- controlled study of baclofen, as an add-on therapy ments, which result in peripheral nerve ablation, usually 2550 Trigeminal Neuralgia, Diagnosis and Treatment result in a short-term remission, but pain usually reoc- muscle weakness. The potential disadvantage is a less curs in 3 to 6 weeks. than 1% mortality rate. Other possible complications Gasserian or trigeminal ganglion  rhizotomy is a include stroke, meningitis, cerebrospinal fluid leak neuroablative procedure performed by inserting a nee- and various ipsilateral cranial nerve deficits, such as dle within the trigeminal cistern. Several neurolytic hearing loss (Slavin and Burchiel 2002). As surgical methods have been developed and are routinely em- microvascular decompression techniques become less ployed, each of them having relative advantages and invasive, such as with endoscopic assistance, it is likely disadvantages. They all provide immediate pain relief that it will become more commonly practised and with in more than 90% of patients. Radiofrequency ther- favorable research published, it may even become a mocoagulation can be directed to a specific division of first-line treatment option. the trigeminal nerve and therefore has the advantage of Due to the varied presentation of trigeminal neuralgia providing a limited and well-controlled lesion. Correct and the reported relapse of positive treatment effects, positioning of the needle tip can be verified by electrical long-termfollow-upandmanagementisessentialinpro- stimulation of the awakened patient prior to lesioning. viding the best possible patient care. Disadvantages of this technique include a potentially higher risk for anesthesia dolorosa and corneal anes- References thesia. Also, other techniques may be superior and 1. Dandy WE (1934) Concerning the cause of trigeminal neuralgia. more practical when large areas of the trigeminal nerve Am J Surg 24 are involved, since multiple lesions will be required. 2. Devor M, Amir R, Rappaport ZH (2002) Pathophysiology of Injection of glycerol as a neurolytic agent is another Trigeminal Neuralgia: The Ignition Hypothesis. Clin J Pain possible approach. Glycerol is thought to affect un- 18:4–13 3. Fromm GH, Chattha AS, Terrence CF et al. (1981) Role of myelinated nerve fibers selectively, thereby sparing inhibitory mechanisms in trigeminal neuralgia. Neurology  proprioception, touch and motor functions of the 31:683–687 trigeminal nerve. Anatomic variations in nerve ablation 4. Fromm GH, Terrence CF, Maroon JC (1984) Trigeminal neural- gia: current concepts regarding etiology and pathogenesis. Arch are achieved by altering the patient’s head position and Neurol 41:1204–1207 adjusting the volume of glycerol injected. The major 5. Fromm GH, Graff-Radford SB, Terrence CF et al. (1990) Pre- disadvantages are the relatively imprecise technique, trigeminal neuralgia. Neurology 40:1493–1495 with the potential of glycerol spreading into the brain, 6. Gilron I, Booher SL, Rowan JS et al. (2001) Topiramate in trigeminal neuralgia: a randomized, placebo-controlled multiple as well as the moderate risk for anesthesia dolorosa and crossover pilot study. Clin Neuropharmacol 24:109–112 corneal anesthesia. Balloon compression is the newest 7. International Headache Society Classification of Headache Dis- technique and has the lowest reported complications orders (2004) Cranial neuralgia, central and primary facial pain, of anesthesia dolorosa and corneal anesthesia (Tekkök and other headache disorders. Cephalalgia Suppl 1:125–135 8. Jannetta PJ (1967) Arterial compression of the trigeminal nerve and Brown 1996). This procedure has the advantage of at the pons in patients with trigeminal neuralgia. J Neurosurg not requiring patient participation, but it has the highest 26:159–162 incidence of muscle weakness and bradycardia requir- 9. Katusic S, Beard CM, Bergstrath E et al. (1990) Incidence and ing pacing has been reported during balloon inflation. clinical features of trigeminal neuralgia, Rochester, Minnesota, 1945–1984. Ann Neurol 27:80–95 Overall, all three techniques provide comparable pain 10. Kitt CA, Gruber K, Davis M et al. (2000) Trigeminal neuralgia: relief and differ mostly in their potential advantages opportunities for research and treatment. Pain 85:3–7 and disadvantages (Slavin and Burchiel 2002). 11. Majoie CB, Hulsmans FJ, Verbeeten B Jr et al. (1997) Trigemi- Stereotactic radiosurgery or gamma knife is a procedure nal neuralgia: comparison of two MR imaging techniques in the demonstration of neurovascular contact. Radiology 204:455–460 performed using radiation to cause nerve injury. The tar- 12. Merskey H, Bogduk N (1994) Relatively localized syndromes of get of treatment is along the trigeminal nerve about 2 to the head and neck. In: Merskey H, Bogduk N (eds) Classification 4 mm after it exits the brainstem at the level of the pons. of chronic pain. IASP Press, Seattle, pp 59–92 13. Sindrup SH, Jensen TS (2002) Pharmacotherapy of trigeminal Advantagesof thistechnique are thatpainrelief percent- neuralgia. Clin J Pain 18:22–27 agesarecomparabletorhizotomyandithasalowriskfor 14. Sist T, Filadora V,Miner M et al. (1997) Gabapentin for idiopathic anesthesia dolorosa and corneal anesthesia. Disadvan- trigeminal neuralgia: report of two cases. Neurology 48:1467 tages include a potential for delayed onset of pain relief 15. Slavin KV, Burchiel KJ (2002) Surgical options for facial pain. In: Burchiel KJ (ed) Surgical management of pain. Thieme, New and high rates of pain recurrence (Slavin and Burchiel York, pp 849–864 2002). 16. Tekkök IH, Brown JA (1996) Trigeminal neuralgia. Neurosurg Microvascular decompression, also known by the Quart 6:267–288 acronym MVD, is an open surgical procedure of the 17. Zakrzewska JM, Hamlyn PJ (1999) Facial pain. In: Crombie IK, Croft PR, Linton SJ et al (eds) Epidemiology of pain. IASP Press, brain. The goal is the alleviation of existing vascular Seattle, pp 171–202 pressure on the trigeminal nerve root. Touted as being 18. Zakrzewka JM, Patsalos PN (2002) Long-term cohort comparing potentially curative, this procedure has initial success medical (oxcarbazepine) and surgical management of intractable rates in pain elimination comparable to those of rhizo- trigeminal neuralgia. Pain 95:259–266 19. Zakrzewka JM, Chaudhry Z, Nurmikko TJ et al. (1997) Lamot- tomy, but it has less pain recurrence and a much lower rigine (lamictal) in refractory trigeminal neuralgia: results from a chance of anesthesia dolorosa, corneal anesthesia and double-blind placebo controlled crossover trial. Pain 73:223–230 Trigeminal Neuralgia, Etiology, Pathogenesis and Management 2551

irritation of the trigeminal nerve leads to focal demyeli- Trigeminal Neuralgia, Diagnostic Method nation, which results in the generation of ectopic action potentials and impaired segmental inhibition. This leads Definition to hyper-excitability of the afferents thatgive rise to pain Diagnosisof trigeminalneuralgia ismade principally on paroxysms as a result of synchronised after-discharge history as there are no diagnostic tests to validate the di- activity. This theory is supported by clinical observa- agnosis. tionsthatpatientswithtrigeminalneuralgiainthemajor-  Trigeminal Neuralgia, Etiology, Pathogenesis and ity of cases are found to have blood vessels compressing Management the trigeminal nerve, either at the nerve root entry zone or less commonly the brain stem. Electron microscopic examination of nerve roots taken from patients with such compressions has revealed focal demyelination in Trigeminal Neuralgia, Etiology, the region of the compression, with close apposition of Pathogenesis and Management demyelinated axons and an absence of intervening glial processes. A process of re-myelination does occur, and JOANNA M. ZAKRZEWSKA this could be responsible for the spontaneous remission Clinical Diagnostic and Oral Sciences, Institute of of the neuralgia. The most effective drugs are anti- Dentistry, University of London, Barts and the London convulsants, and they probably work by suppressing ec- Queen Mary’s School of Medicine & Dentistry, topic hyper-excitability in the nerve or central neurons. London, UK [email protected] Clinical History The following list provides the diagnostic criteria as Synonyms suggested by the International Headache Society (Anon 1988) ( trigeminal neuralgia, diagnostic method): Trigeminal neuralgia; tic douloureux; Secondary Trigeminal Neuralgia; Symptomatic Trigeminal Neu- 1. Paroxysmal attacks of facial or frontal pain last a few ralgia; Atypical Trigeminal Neuralgia seconds to less than two minutes. 2. Pain has at least 4 of the following characteristics: Definition – Distributionalongoneormoredivisionsoftrigem- The International Association for the Study of Pain inal nerve (IASP) defines trigeminal neuralgia as “A sudden, usu- – Sudden, intense, sharp, superficial, stabbing or ally unilateral, severe, brief, stabbing, recurrent pain burning in quality in the distribution of one or more branches of the fifth – Pain intensity severe cranial nerve” (Merskey and Bogduk 1994). – Precipitation from trigger areas, or by certaindaily activities such as eating, talking, washing the face Characteristics or cleaning the teeth Epidemiology – Between paroxysms entirely asymptomatic T  The incidence of trigeminal neuralgia is 4.3/100,000 3. No neurological deficit. (2.96 male, 3.47 female/100,000 based on data from the 4. Attacks are stereotyped in individual patients. US). The point prevalence is 0.1%. The peak incidence 5. Exclusion of other causes of facial pain. is in the age group 60–69, and it is rare in patients un- der the age of 40. There is a strong link between multi- It is essential to take a very careful history, as this is the ple sclerosis and trigeminal neuralgia, and hypertension only reliable method of making the diagnosis. It is es- may also be a risk factor. There are little data on the natu- pecially important to elucidate the sharpness and parox- ral history and prognostic features ( trigeminal neural- ysmal quality of this pain, which differentiates it from gia, features), but data from the US suggests that it does most other facial pains. A particular feature of trigem- notaffectsurvival,althoughattacksgetmoreseverewith inal neuralgia is that it is usually precipitated from one time (Zakrzewska and Hamlyn 1999). or more trigger areas (especially in the second or third trigeminal divisions), upon tactile stimulation or daily Etiology and Pathogenesis activities such as eating, talking, washing or shaving the As there are no satisfactory animal models of trigeminal face or cleaning the teeth. Each boutof painisvery quick neuralgia, it still remains difficult to elucidate fully the (seconds), but patients may get many of these in quick aetiology and pathogenesis of trigeminal neuralgia. The succession,andsothepainmayseemtobelastinglonger. ignition hypothesis by Devor et al. (2002) ( trigeminal The nerve eventually becomes refractory and there is a neuralgia,ignitiontheory)isacceptedbymany,although period when the patient is pain free. Classically, there direct support of it from trigeminal electrophysiological are also periods of complete pain remission which last studies is very limited. According to this theory, chronic for weeks or months. These pain remissions gradually 2552 Trigeminal Neuralgia, Etiology, Pathogenesis and Management

Trigeminal Neuralgia, Etiology, Pathogenesis and Management, Table 1 Medical management of trigeminal neuralgia, most drugs need to be escalated and withdrawn slowly Drug Daily dosage Outcome Number Side effects, Number needed to harm Comments range needed to treat NNT NNH(95% CI) (95% CI)

Baclofen 50–80 mg NNT 1.4 (1–2.6) only Ataxia, lethargy, fatigue, nausea Useful as add on therapy 10 patients, possibly effective

Carbamazepine 300–1200 mg NNT 2.6 ( 2–4) , Ataxia, dizziness, diplopia, lethargy NNH 3.4 Reduced white cell count, effective (2.5–5.2) for side effects, NNH for withdrawal hyponatraemia higher doses 24 (13–110)

Lamotrigine 200–400 mg NNT 2.1 ( 1.3–6.1) as dizziness, drowsiness, constipation, ataxia, Rapid dose escalation add on medication diplopia, irritability increases incidence of rashes

Pimozide 4–12 mg NNT 2 (2–3) Extrapyramidal e.g. tremor, rigidity NNH 2.9 Side effects too severe to (2–4) recommend routine use

Proparcaine 2 drops of Not effective Toxic keratopathy in long term use Short lasting even if given 0.5% solution repeatedly

Tizanidine 6–18 mg May be effective Nil reported Effect is short lasting

Tocainide 60 mg/kg Not effective Nausea, parasthesia, rash Risk of aplastic anaemia precludes its routine use

Drugs evaluated in case reports only none over 25 patients Capsaicin topical mg for 21–28 Little benefit Burning sensation Temporary relief ,avoid on skin days contact with the eye

Clonazepam 2–8 mg May be effective Lethargy in 60%, fatigue, dizziness, Thromocytopenia can occur personality change

Gabapentin 1200– May be effective Ataxia, dizziness, drowsiness, nausea, Better tolerated than 3600 mg headache carbamazepine

Oxcarbazepine 300–1200 mg Effective Ataxia, dizziness, diplopia, lethargy which Better tolerated than with may be related to hyponatraemia dose carbamazepine dependent

Phenytoin 200 – 300 mg Effective Ataxia, lethargy, nausea, headache, Small margin for dose behavioural changes , folate deficiency in escalation prolonged use, gingival hypertrophy

Valproic acid 600 – 2000 mg May be effective Irritability, restlessness, tremor, confusion, nausea, rash, weight gain get shorter and shorter. The most common divisions to will have, what are termed, atypical features and will re- be affected are the second and third, and it is rare for the port a constant, dull, aching background pain, exhibit no firstdivision aloneto beaffected. In about3%ofpatients paroxysmal features, or have no pain free periods. Some thepainbecomesbilateral,butitisunusualforbothsides of these symptoms may be related to stress and anxiety. to be active at the same time. Although 70% of patients will gain relief of pain from Other features that need to be assessed include the qual- the use of carbamazepine, this is not always diagnostic. ity of life and the level of anxiety and depression. Most patients with severe trigeminal neuralgia find it impos- Examination sible to socialise because of fear of developing an at- In most patients, neurological examination will benega- tack of pain while eating. These patients will often lose tive but some subtle sensory changes may be present. In weight and become depressed. Ideally, patients should some cases, this could indicate that there is a secondary be evaluated with standard assessment measures such causefortrigeminalneuralgia.Itisimportanttoexamine as the McGill Pain Questionnaire, some form of anx- the oral cavity to exclude any dental causes for pain, es- iety or depression scale such as the Hospital Anxiety peciallyifthepatientreportsintra-oralpain.Assessment and Depression Scale, and a quality of life assessment of hearing may be important if patients wish to undergo such as the Brief Pain Inventory or SF36. Some patients an operation that carries a risk of causing hearing loss. Trigeminal Neuralgia, Etiology, Pathogenesis and Management 2553

Investigation Table 1 gives an indication of the drugs that are in use. There are no diagnostic tests for trigeminal neuralgia. A Patients should be encouraged to keep pain diaries so CT scan can be used to look for evidence of secondary they learn to take control of their medication. Once the causes such as benign or malignant tumours or cysts. patient has become pain free for a month, the drugs MRIscanswillalsoshowwhetherthereisacompression should be slowly tapered off in the hope that the patient of the nerve by blood vessels. However, their specificity has gone into a natural remission period. Patients, how- and sensitivity in being able to predict operative findings ever, need to be warned that they should re-start their still remain under investigation. medication as soon as they develop new paroxysms of pain. Management Surgery Trigeminal neuralgia is a rare condition, and although it can be treated in its initial phases in primary care, Major indications for referring patients for surgery most of these patients benefit from being referred to the include inability to control the pain, poor quality of secondary care sector, to clinicians who specialise in life, and side effects from medication. Surgery can be the management of this condition. Patients, themselves, carried out at three levels, at the peripheral level where should be well-informed about the condition since com- treatments are aimed at the trigger points, at the level pliance and satisfaction have beenshowntobeimproved of the Gasserian ganglion which involves ablative pro- in those patients who have a better understanding of cedures, and at the level of the posterior fossa where their condition, and are given an opportunity to express one procedure is ablative whereas the other, that of their wishes in terms of treatment. The  expert patient microvascular decompression ( trigeminal neuralgia, is also able to give truly informed consent to treatment. microvascular decompression), is non-ablative. All ab- Most patients will initially be managed medically and lative surgery ( trigeminal neuralgia, types of ablative then surgery will be offered as a secondary procedure. surgery) is likely to result in sensory loss in the area of There remains considerable debate as to the best timing the trigeminal nerve as tactile, thermal and pain fibres of surgery. may be destroyed. There are no randomised controlled trials of surgical treatments, and the quality of data re- Medical management (trigeminal neuralgia, medical porting outcomes after surgical treatments is relatively management) poor (Zakrzewska and Lopez 2003). However, there is The mainstay of treatment for this condition is the use general consensus that the more central the procedure, of anti-convulsants, and carbamazepine is the only drug the more likely patients are to gain long-term pain relief that has been the subject of three randomised, con- and high satisfaction rates (Zakrzewska 2002). Table 2 trolled trials (McQuay et al. 1995; Wiffen et al. 2005; provides data on different surgical procedures (Burchiel Zakrzewska and Lopez 2005). It therefore remains the 1999; Maesawa et al. 2001; Nurmikko and Eldridge gold standard against which other drugs are evaluated. 2001). T Trigeminal Neuralgia, Etiology, Pathogenesis and Management, Table 2 Surgical management of trigeminal neuralgia (  trigeminal neuralgia, aims of surgical management ), data on 5 years not available for some procedures, sensory loss common in all Gasserian ganglion* procedures Procedure % Probability of being Mortality Morbidity pain free

Peripheral neurectomy, cryother- Two years: 22 Nil Low, sensory loss, transient haematoma, oedema apy, alcohol, injection, acupunc- ture Radiofrequency thermorhizotomy Two years: 68 Low 28% complications mainly relating to trigeminal nerve, (RFT) * Five years: 48 dyseasthesia, anesthesia dolorosa, eye problems, masseteric problems

Percutaneous glycerol rhizotomy* Two years: 63 Low 25% complications as for RFT Five years: 45

Balloon microcompression* Two years: 79 Low 10% complications as for RFT

Microvascular decompression Two years: 81 0.5% Overall 75% no complications, 14% peri-operative complications, Five years: 76 5% transient cranial nerve 4th,6th,8th dysfunction, 2% permanent Ten years: 71 deafness

Gamma Knife surgery Two years: 58 Nil Late onset of relief, may only be partial, 8% sensory loss up to two years post treatment 2554 Trigeminal Neuralgia, Ignition Theory

Patient Information and Support (trigeminal neuralgia, patient information) Trigeminal Neuralgia, Medical There is now a considerable amount of literature on Management trigeminal neuralgia for patients in the English lan- guage. The information is in the form of printed articles Definition as well as a book (Weigel and Casey 2000), and there is Medical management of trigeminal neuralgia is princi- a considerable body of data on the internet produced by pally with the use of anticonvulsantdrugs, few of which patient support groups (www.tna-uk.org.uk; www.tna- haveundergoneevaluationunderrandomizedcontrolled support.org). Patients need to be aware that continuing trial conditions. care may be necessary and not everyone can be cured.  Trigeminal Neuralgia, Etiology, Pathogenesis and Management References 1. Anonymous (1988) Classification and Diagnostic Crite- ria for Headache Disorders, Cranial Neuralgias and Facial Pain. Headache Classification Committee of the International Trigeminal Neuralgia, Microvascular Headache Society. Cephalalgia 8:1–96 Decompression 2. Devor M, Amir R, Rappaport ZH (2002) Pathophysiology of Trigeminal Neuralgia: the Ignition Hypothesis. Clin J Pain 18:4–13 Definition 3. Burchiel KJ (1999) (ed) Trigeminal Neuralgia in Techniques in Neurosurgery 5:200–266 Series of Articles by variety of authors Microvascular decompression is a major neurosurgical 4. Maesawa S, Salame C, Flickinger JC et al. (2001) Clinical Out- procedure that involves gaining entry into the posterior comes after Stereotactic Radiosurgery for Idiopathic Trigeminal fossaoftheskull,andidentifyinganddecompressingthe Neuralgia. J Neurosurg 94:14–20 5. McQuay H, Carroll D, Jadad AR et al. (1995) Anticonvulsant trigeminal nerve in order to provide pain relief without Drugs for Management of Pain: A Systematic Review. BMJ sensory loss. 311:1047–1052  Trigeminal Neuralgia, Etiology, Pathogenesis and 6. Merskey H, Bogduk N (1994) Classification of Chronic Pain. Management Descriptors of Chronic Pain Syndromes and Definitions of Pain Terms. IASP Press, Seattle 7. Nurmikko TJ, Eldridge PR (2001) Trigeminal Neuralgia – Patho- physiology, Diagnosis and Current Treatment. Br J Anaesth 87:117–132 Trigeminal Neuralgia, Patient Information 8. Weigel G, Casey KF (2004) Striking Back – The Trigeminal Neu- ralgia and Face Pain Handbook. Whitehall Printing Company, Definition Naples, Florida 9. Wiffen PJ, McQuay HJ, Moore RA (2005) Carbamazepine for There is a considerable amount of information, both acute and chronic pain. The Cochrane Database of Systematic written and electronic, on trigeminal neuralgia for both Reviews: Reviews 2005. Issue 3 John Wiley & Sons, Ltd. Chich- ester, UK DOI.:10.1002/14851858.CD005451 healthcare workers and patients, which would aid in 10. Zakrzewska JM (2002) Trigeminal Neuralgia. In: Zakrzewska management. JM, Harrison SD (eds) Assessmentand Management of Orofacial  Trigeminal Neuralgia, Etiology, Pathogenesis and Pain. Elsevier Sciences, Amsterdam, pp 267–370 11. Zakrzewska JM, Hamlyn PJ (1999) Facial Pain. In: Crombie Management IKCPR, Linton SJ, LeResche L et al. (eds) Epidemiology of Pain. IASP Press, Seattle, pp 171–202 12. Zakrzewska JM, Lopez BC (2003) Quality of Reporting in Eval- uations of Surgical Treatments of Trigeminal Neuralgia: Recom- Trigeminal Neuralgia, Types of Ablative mendations for Future Reports. Neurosurgery 53:110–122 13. Zakrzewska JM, Lopez BC (2005) Trigeminal Neuralgia. Clin Surgery Evid 14:1669–1677 Definition Ablative surgery for trigeminal neuralgia involves se- lective destruction of the trigeminal nerve, and many of Trigeminal Neuralgia, Ignition Theory these procedures can be done in elderly medically un- fit patients, but most result in facial sensory loss. These procedures include radiofrequency thermocoagulation Definition (electrically heating the Gasserian ganglion), percuta- Trigeminal neuralgia is thought to be caused by chronic neous glycerol injection (injecting glycerol round the irritation of the trigeminal nerve, which leads to ectopic Gasserian ganglion) or balloon microcompression (ap- hyperexcitability,and this is the basis of the ignition hy- plying pressure on the Gasserian ganglion for a few sec- pothesis. onds).  Trigeminal Neuralgia, Etiology, Pathogenesis and  Trigeminal Neuralgia, Etiology, Pathogenesis and Management Management Trigeminal, Glossopharyngeal, and Geniculate Neuralgias 2555

Synonyms Trigeminal Nucleus Caudalis Trigeminal neuralgia: tic douloureux, Fothergill’s dis- ease, epileptiform neuralgia Definition Glossopharyngeal neuralgia: vagoglossopharyngeal Part of the trigeminal nuclei that relays intracranial no- neuralgia ciceptive information to higher integrative centers. Nervus Intermedius, Primary Otalgia  Brainstem Subnucleus Reticularis Dorsalis Neuron Definitions Cranial neuralgias are idiopathic chronic pain con- Trigeminal Subnucleus Caudalis ditions characterized by sudden, often short-lived, episodes of pain that may result from non-painful Definition cutaneous stimulation, and that involve the distribu- tions of the involved trigeminal, glossopharyngeal, or Trigeminal subnucleus caudalis is the most caudal com- geniculate nerve branches. ponentofthetrigeminalsystem,continuouswiththedor- sal horn of the spinal cord.  DentalPain, Etiology, PathogenesisandManagement Characteristics Epidemiology is challenged by the lack of consistently applieddiagnosticcriteria,theabsenceofobjectivemea- Trigeminal Tractotomy sures, and the variety of facial pain syndromes encoun- tered by the clinician (Kitt 2000). Trigeminal neuralgia (TN) is the most common cranial neuralgia. Studies in Definition Minnesota report a TN incidence rate of approximately A surgical procedure to sever the V spinal tract. The le- 5/100,000 population (Katusic et al. 1991). Rates are sion also involves some lateral part of Vc. When per- higher in women, 5.9 vs 3.4. The ratio of glossopharyn- formed in humans, the purpose is to deprive Vc of the geal neuralgia (GN) has been reported to be from 5 to inputs from the primary afferents, and therefore to pro- 200-fold less than TN. Geniculate neuralgia (GenN) is vide relief to patients from the excruciating pain of V considered rare, with experienced neurosurgeonsreport neuralgia. seeing 10–15 GenN cases among several thousand cases  Trigeminal Brainstem Nuclear Complex, Physiology of cranial neuralgias. Cranial neuralgias are usually diseases of seniors (IHS 1997). The median age of diagnosis in the Minnesota series was 67 (Katusic et al. 1991), although the range Trigeminal Transition Zone is wide and younger patients are common, especially in multiple sclerosis (see  Central Pain in Multiple Scle- Definition rosis). A few series and case reports have described fa- T A region at the obex level where the subnuclei interpo- milial occurrences of TN, although no specific genetic laris (Vi) and caudalis (Vc) of the spinal trigeminal nu- defects have been identified, and no linkage studies of cleus converge. The ventral portion of the laminated Vc these families have been performed. An aggregation of is pushed dorsomedially by Vi. The substantia gelati- the case reports shows that family members tend to be nosa is still identifiable but often interrupted. Neurons afflicted on the same side of the face, have a tendency to in the trigeminal transition zone project to the thalamus, develop bilateral TN, have a younger age of onset (44.4 and are involved in processing of nociceptive informa- years), and tend to demonstrate an autosomal dominant tion from the orofacial regions. mode of transmission with reduced penetrance (Fleet-  Trigeminothalamic Tract Projections wood 2001). The known causes of TN include demyelinating dis- easessuch asmultiple sclerosis, infiltration of the root or Gasserian ganglion by tumor or amyloid deposition, or Trigeminal, Glossopharyngeal, and small pontine or medullary infarcts (Love and Coakham Geniculate Neuralgias 2001). About 4% of TN patients have multiple sclero- sis, and 1–5% of multiple sclerosis patients develops WILLIAM S. ANDERSON,CAROL JAMES, TN (Nurmikko and Eldridge 2001). The majority of BENJAMIN S. CARSON SR. cases are believed to be due to nerve compression ef- Department of Neurological Surgery, Johns Hopkins fects, usually by vascular structures (80–90%) (Love Hospital, Baltimore, MD, USA and Coakham 2001). A recent operative series of mi- [email protected] crovascular decompression procedures showed that 2556 Trigeminal, Glossopharyngeal, and Geniculate Neuralgias

90% of first operations revealed compression of the mandibular division TN. The trigger can be swallowing, nerve root by either an artery or vein, while in the rest yawning, clearing the throat, or talking. GN, like TN, is of the cases compression of the root was caused by generally unilateral although there are reports of bilat- arachnoid thickening, or angulation or torsion of the eral GN, GN with TN, and atypical cases. root axis (Ishikawa et al. 2002). Approximately 70% GenN is a very rare condition, which is characterized by of this series had arterial compression, of which 82% deep pain affecting the distribution of the nervus inter- were caused by the superior cerebellar artery (SCA). medius: inner ear with radiation to parts of the face with More than 9% had demonstrable venous compression. the pinna of the ear being the most common spot. Un- Herpes zoster is commonly associated with outbreaks. like trigeminal neuralgia, the pain can last for hours at a The causes of GN and GenN may be similar to that of time, but like trigeminal neuralgia spontaneous remis- TN because effective therapies are similar, but direct ev- sions can occur. Pain can be triggered by non-noxious idenceislacking. Severalgroupshavestudiedthepatho- stimuli of the ear canal, swallowing, or talking (Loeser logic consequences of trigeminal nerve root compres- 1990). sion. Devor et al. describe areas of axonal loss and de- myelination close to the compressing vessel with an in- Pharmacological Treatments crease in number of astrocytic processes, a froth of li- Patients who present with TN are initially treated posomes (the residual myelin sheaths) as well as large with medication, and the first line drug therapy is and small diameter denuded axons (Devor et al. 2002). carbamazepine, with typical maintenance doses of Clumps of pure collagen are found in the demyelination 1500–2000 mg/day (Sindrup and Jensen 2002). Carba- zone, as well as regions of dysmyelination in the root mazepine was shown to be effective at reducing pain adjacent to the offending vessel. The length of a given severity, number of paroxysms, and number of triggers  cranial nerve central nervous system (CNS) portion in approximately 75% of patients. Side effects include may be associated with the incidence of neuralgia af- sedation, rash, hyponatremia, and rarely agranulocy- fecting that cranial nerve (De Ridder et al. 2002). For in- tosis. Many clinicians have switched their patients to stance, TN hasa higher incidence than hemifacialspasm oxcarbamazepine, a keto-derivative of carbamazepine (CN VII), which has a higher incidence than GN, co- with a lower side-effect profile, and less chance of varying with the central segment of the involved nerve hematologic problems. identified by oligodendroglial cell derived myelin. The Phenytoin is often used as a second-line agent, but few CNS portion of the nerve may be subject to injury by controlledtrialshavebeenperformedwiththisdrug;typ- compression because it lacks the strong fascicular struc- ical maintenance doses are 300–400 mg/day (Sindrup ture of the peripheral nerve system portion (De Ridder and Jensen 2002). Baclofen has also been used for pain et al. 2002). The relief many patients feel immediately control in these syndromes. Newer anti-epileptic drugs after decompressive surgery is too short for remyelina- have also been investigated. Lamotrigine, as an add-on tion to be a mechanism. More likely, relief may relate drug to either carbamazepine or Phenytoin, was shown to a decrease in ectopic pulse generation, to an increase to be effective. in fiber separation brought about by the decompression, The relative roles of pharmacotherapy and surgery (see and to the rapid reversal of conduction blockade in the below) for TN are in a state of flux, although certainly remaining myelinated fibers(Love andCoakham 2001). medically refractory patients tend to progress to surgery more quickly. A few authors have argued that surgery Clinical Features should be utilized earlier, before the typical TN features TN is characterized by a painful sensation in the face, evolve into the atypical features of constant background characterized by paroxysms of electric shock like pain painandsensorydisturbances,whileothersquestionthis within one or more of the trigeminal nerve divisions. theoryofdiseaseprogression. Manyreportsobservethat The pain can occur spontaneously, or be elicited by non- the pharmacotherapy of GN and the rare GenN are the noxious stimuli such as touch, talking, eating, or wind. same as TN. The pain is acute in onset and termination, and may show periods of remission (IHS 1997). Pain is usually Surgical Treatment unilateral, but bilateral cases are observed. Neurologic Surgical therapy of TN includes an assortment of treat- deficits are generally absent. Case reports of atypical ments, ranging from relatively low invasive therapies TN are common. such as stereotactic radiosurgery, peripheral nerve Severe paroxysmal pain in the sensory domain of the branch procedures including peripheral neurectomy, glossopharyngeal nerve is similar to TN, except for the foraminal neurectomy and occlusion, or cryotherapy, position within the distribution of the auricular and pha- percutaneous ganglion level procedures including RF ryngeal branches of the vagus nerve and that of the glos- thermocoagulation, glycerolysis, balloon compression, sopharyngealnerve:theposteriorpartofthetongue,ton- and  microvascular decompression (MVD) proce- sillar fossa, pharynx, beneath the angle of the lower jaw, dures. These latter procedures involve a suboccipital or in the ear (Loeser 1990). GN may be mistaken for craniectomy to reverse vascular compressive of the Trigeminocervical Complex 2557 nerve. Jannetta and coworkers described the largest se- ryngealcocaineblockspriortoattemptingnervesection- ries of cranial neuralgias treated with MVD, including ing. Long-term results for surgical treatment of GenN in TN and GN (McLaughlin et al. 1997). 64 patients have been reviewed by Pulec (Pulec 2002). Reviews of the various surgical treatments have gener- ally found that ganglion level procedures tended to be References moreeffectivethanperipheralprocedures;however,nei- 1. De Ridder D, Møller A, Verlooy J, Cornelissen M, De Ridder L ther group produced long-term pain relief. For instance, (2002) Is the Root Entry/Exit Zone Important in Microvascular RF thermocoagulation by itself provided initial pain re- Compression Syndromes? Neurosurgery 51:427–434 lief rates of 91–99% with subsequent recurrence rates of 2. Devor M, Govrin-Lippmann R, Rappaport ZH (2002a) Mech- 10–25% over the various study times (25% at 14 years), anism of Trigeminal Neuralgia: An Ultrastructural Analysis of Trigeminal Root Specimens Obtained During Microvascular De- while peripheral neurectomy by itself had a success rate compression Surgery. J Neurosurg 96:532–543 of only 64% at one year, which fell to 26% by 4 years 3. Fleetwood IG, Innes AM, Hansen SR, Steinberg GK (2001) Fa- (Peters and Nurmikko 2002). milial Trigeminal Neuralgia: Case Report and Review of the Lit- erature. J Neurosurg 95:513–517 An emerging treatment for TN is stereotactic radio- 4. International Headache Society (IHS) (1997) Member’s Hand- surgery. Pollock et al. published a series of 117 patients book 1997/98: Classification and Diagnostic Criteria for with an average age of 67.8 years, 58% of whom had Headache Disorders, Cranial Neuralgias, and Facial Pain. a previous surgical treatment. An excellent outcome Scandinavian University Press, Oslo, pp 102–103 5. Ishikawa M, Nishi S, Aoki T, Takase T, Wada E, Ohwaki H, Kat- overall (complete pain relief without medication) was suki T, Fukuda H (2002) Operative Findings in Cases of Trigemi- achieved of 57% at 1 year, and 55% at 3 years. Factors nal Neuralgia Without Vascular Compression: Proposal of a Dif- associated with a good outcome were normal preoper- ferent Mechanism. J Clin Neurosci 9:200–204 ative facial sensation, increased radiation dosage, no 6. Kastusic S, Williams DB, Beard CM, Bergstralh EJ, Kurland LT (1991) Epidemiology and Clinical Features of Idiopathic Trigem- prior surgery, and trigeminal dysfunction/numbness. inal Neuralgia and Glossopharyngeal Neuralgia: Similarities and Negative factors included multiple sclerosis and atypi- Differences, Rochester, Minnesota, 1945–1984. Neuroepidemi- cal pain features. These authors stress that since the long ology 10:276–281 term effects of radiation therapy close to the brainstem is 7. Loeser JD (1990) In: The Management of Pain, vol 1, 2nd edn. Cranial Neuralgias, Lea & Febiger, Philadelphia unknown, first line treatment for young healthy patients 8. Love S, Coakham HB (2001) Trigeminal Neuralgia: Pathology should continue to address the vascular compressive and Pathogenesis. Brain 124:2347–2360 lesion via an MVD procedure (Pollock et al. 2002). 9. McLaughlin MR, Jannetta PJ, Clyde BL, Subach BR, Comey CH, Patel et al. (2002) reviewed the experience of 217 pa- Resnick DK (1997) Microvascular Decompression of Cranial Nerves: Lessons Learned after 4400 Operations. J Neurosurg tients who underwent MVD for GN neuralgia between 90:1–8 1973 and 2000. In this group, immediate relief (no pain, 10. Nurmikko TJ, Eldridge PR (2001) Trigeminal Neuralgia: and no medication) was obtained by 67% and partial Pathophysiology, Diagnosis and Current Treatment. Br J Anaes relief by 25%, while the long-term results showed com- 87:117–132 11. Patel A, Kassam A, Horowitz M, Chang Y-F (2002) Microvas- plete relief 58% and partial relief 18%. Complications cular Decompression in the Management of Glossopharyngeal of the procedure were few and included intracranial Neuralgia: Analysis of 217 Cases. Neurosurgery 50:705–711 hematoma, brainstem infarction, cranial nerve palsy, 12. Peters G, Nurmikko TJ (2002) Peripheral and Gasserian CSF leak, operative death (none since 1987), and dys- Ganglion-Level Procedures for the Treatment of Trigeminal T Neuralgia. Clin J of Pain 18:28–34 phagia, and seemed to decrease over time (Patel et al. 13. Pollock BE, Phuong LK, Gorman DA, Foote RL, Stafford SL 2002). (2002) Stereotactic Radiosurgery for Idiopathic Trigeminal Neu- SurgeryforGenNisbasedontheconceptthatpainisme- ralgia. J Neurosurg 97:347–353 14. Pulec JL (2002) Geniculate Neuralgia: Long-Term Results of diated through the nervous intermedius and the genic- Surgical Treatment. Ear Nose Throat J 81:30–33 ulate ganglion. In general, rare conditions such as this 15. Sindrup SH, Jensen TS (2002) Pharmacotherapy of Trigeminal should be referred to individuals who have had signifi- Neuralgia. Clin J of Pain 18:22–27 cant experience with them, since historically morbidity associated with surgical treatment of this condition is relatively high. The surgical treatment involves dissect- ing out the nervous intermedius from the seventh cra- nial nerve in the cerebellar pontine angle and section- Trigeminocervical Complex ing it. Variable results have been reported with MVD. One of the major problems with GenN is distinguishing Definition it from GN or even from TN, which affects the third divi- sion of the nerve. This confusion has led some to advo- Neurons in the trigeminal nucleus caudalis and dorsal cate not only cutting the nervous intermedius, but also horn of spinal cord segments C1 and C2, which act to- the glossopharyngeal nerve and the upper third of the gether as a functional relay for pain input from intracra- vagus nerve. Unfortunately, there are no specific tests nial structures, and overlap with input from the front and that are guaranteed to predict surgical success, although back of the head. some otolaryngologists feel that it is useful to do pha-  Migraine, Pathophysiology 2558 Trigeminohypothalamic Tract

The trajectory and termination of the trigeminohypotha- Trigeminohypothalamic Tract lamic tract have been examined using antidromic acti- XIJING J. ZHANG vation (Malick et al. 2000). The trigeminohypothalamic Department of Neuroscience, University of Minnesota, axons cross the midline and ascend on the contralateral Minneapolis, MN, USA side of the brainstem to the level of the contralateral [email protected] thalamus. Within the thalamus, trigeminohypothalamic axons shift through the optic tract, internal capsule, and supraoptic decussation and reach the rostral ven- Definition tral hypothalamus. In the rostral ventral hypothalamus The trigeminohypothalamic tract is a bundle of nerve more than half of the axons cross the midline again at fibersoriginatingfromallofthesubnucleiofthetrigemi- the posterior optic chiasm to the ipsilateral hypotha- nalbrainstemnuclearcomplexandthegraymatterofup- lamus, turn caudally and descend along the identical percervicalspinalcordsegments(C1–2),andprojecting path in which they ascended in the contralateral hy- to or through the hypothalamus. The trigeminohypotha- pothalamus (Malick et al. 2000). The axons of the lamic tract is responsible for conveying sensory infor- trigeminohypothalamic neurons and their collateral mation, especially nociceptive information, from facial branches terminate bilaterally in many nuclei within skin, cornea, oral mucosa, and intracranial dura to the hypothalamus, such as the lateral, perifornical, dorso- hypothalamus, a brain area that regulates homeostasis medial, suprachiasmatic, and supraoptic hypothalamic and other hormonal responses required for survival of nuclei (Malick et al. 2000). Through this complex the organism. projection, the axons of the trigeminohypothalamic neurons are capable of carrying nociceptive informa- tion bilaterally to many nuclei in the hypothalamus that Characteristics are involved in the production of various responses to Anatomical retrograde labeling and physiological noxious stimuli. antidromic activation techniques have identified the Responses of the trigeminohypothalamic neurons to locations of the trigeminohypothalamic neurons in the noxiousstimulihavebeendescribed(Malicketal.2000). trigeminal brainstem nuclear complex and the gray mat- The overwhelming majority of the trigeminohypothala- ter of upper cervical spinal cord segments (Malick and mic neurons responded strongly to noxious mechanical Buratein 1998; Malick et al. 2000). After the retrograde and thermal stimuli applied to the skin. The receptive tracer Fluoro-Gold injection into the hypothalamus, fields of the trigeminohypothalamic neurons included trigeminohypothalamic neurons are found throughout the skin of the head and neck, as well as orofacial all of the subnuclei of the trigeminal brainstem nuclear organs such as the oral mucosa, tongue, lips, cornea, complex (56%) and upper cervical spinal cord seg- and intracranial dura. Laminae I-II neurons gener- ment (44%) (Malick and Buratein 1998). Within the ally exhibited small to medium receptive fields, while trigeminal brainstem nuclear complex, over 75% of the those located in deeper layers had medium to large neurons were distributed caudal to the obex; most of the receptive fields. Over 80% of the recorded trigemi- neurons were located in the nucleus caudalis. Over 90% nohypothalamic neurons were nociceptive. Among of the neurons in the nucleus caudalis were distributed them, 42% were wide dynamic range, and 38% were in laminae I, II and V.The nucleus caudalis is the subnu- high-threshold neurons. The remaining 20% were low- cleus in the trigeminal brainstem nuclear complex that threshold neurons (Malick et al. 2000). Figure 1 shows processes nociceptive information arising in oral and that a high-threshold trigeminohypothalamic neuron facial organs (Sessle 1987; Jacquin et al. 1986). In cer- responded to noxious mechanical stimulus applied to vical cord segments 1 and 2, approximately 85% of the its receptive field. The neuron was located in dorsome- neurons were found in laminae I, II and V. These areas dial lamina V of the nucleus caudalis (b), and its axon receive direct input from trigeminal primary afferent projected to the contralateral hypothalamus (a). The fibers and contain neurons that respond to mechanical neuron had a small cutaneous receptive field located or thermal stimulation of the cornea, oral mucosa, tem- around the ipsilateral side of the mouth (c), and only poromandibular joint, facial skin, and intracranial dura responded to noxious mechanical stimuli applied to the (Lu et al. 1993; Broton et al. 1988, Burstein et al. 1998). skin (d). Trigeminohypothalamic neurons were also recorded The majority of nociceptive neurons responded primar- in laminae I, II and IV, V of the nucleus caudalis, and ily to noxious intensities of thermal stimulation. In con- upper cervical (C1) spinal cord by physiological an- trast, all low-threshold neurons responded to both heat tidromic activation studies (Malick et al. 2000). Most of and cold stimuli at innocuous and noxious intensities, a the trigeminohypothalamic neurons that were recorded phenomenon that has not been reported for other pop- responded maximally or exclusively to noxious me- ulations of spinal or trigeminal low-threshold neurons chanical or thermal stimulation to the head and orofacial (Malick et al. 2000). Thus, trigeminohypothalamic neu- receptive fields innervated by the trigeminal nerve. rons can transmit innocuous and primarily noxious me- Trigeminohypothalamic Tract 2559

Trigeminohypothalamic Tract, Figure 1 Response property of a high-threshold trigeminohypothalamic neuron. (a) Location of low-threshold point for antidromic activation in the hypothalamus. (b) Recording site in dorsomedial lamina V. (c) Receptive field. (d) Peristimulus histogram and record of window discriminator output (below histogram) illustrating the response to mechanical stimuli applied to the receptive field. Numbers in parentheses depict mean response (spikes/sec) to each stimulus. (From Malick et al. 2000). Hyp, hypothalamus; IC, internal capsule; VBC, ventrobasal complex.

chanical and thermal information from facial skin di- related autonomic responses, endocrine adjustments, rectly to the hypothalamus. or emotion reactions. Many trigeminohypothalamic neurons were also pow- erfully activated by electrical and mechanical stimuli of the oral mucosa, tongue, lips, cornea, and intracranial T dura mater (Malick et al. 2000). Most (85%) oral- References sensitive trigeminohypothalamic neurons encoded the 1. Broton JG, Hu JW, Sessle BJ (1988) Effects of Temporomandibu- intensity of the noxious mechanical and thermal stim- lar Joint Stimulation on Nociceptive and Non-Nociceptive Neu- rons of the Cat’s Trigeminal Subnucleus Caudalis (Medullary uli. Since pain is the only sensation that can be evoked Dorsal Horn). J Neurophysiol 59:1575–1589 by stimulating the cornea and intracranial dura and 2. Burstein R, Yamamura H, Malick A, Strassman AM (1998) sinuses, regardless of whether the stimulus is electrical, Chemical Stimulation of the Intracranial Dura Induces Enhanced mechanical, or chemical (Lele and Weddell 1959, Ray Responses to Facial Stimulation in Brainstem Trigeminal Neu- rons. J Neurophysiol 79:964–982 and Wolff 1940), the cornea- and dura-sensitive neurons 3. Jacquin MF, Renehan WE, Mooney RD, Rhoades RW (1986) were considered nociceptive. Therefore, trigeminohy- Structure-Function Relationships in Rat Medullary and Cervical pothalamic neurons can transmit nociceptive infor- Dorsal Horns. I. Trigeminal Primary Afferents. J Neurophysiol 55:1153–1186 mation from these specific organs in the head to the 4. Lele PP, Weddell G (1959) Sensory Nerves of the Cornea and hypothalamus. Cutaneous Sensibility. Exp Neurol 1:334–359 The hypothalamus plays an important role in regulating 5. Lu J, Hathaway CB, Bereiter DA (1993) Adrenalectomy En- body temperature, food and water intake, sleep and hances Fos-Like Immunoreactivity within the Spinal Trigeminal Nucleus Induced by Noxious Thermal Stimulation of the Cornea. circadian rhythms, endocrine adjustments, and a wide Neuroscience 54:809–818 range of behavior (Swanson 1987). Through the termi- 6. Malick A, Buratein R (1998) Cells of Origin of the Trigemino- nations and collateral branches in the hypothalamus, the hypothalamic Tract in the Rat. J Comp Neurol 400:125–144 trigeminohypothalamic tract is likely to bring noxious 7. Malick A, Strassman AM, Burstein R (2000) Trigeminohypotha- lamic and Reticulohypothalamic Tract Neurons in the Upper Cer- and innocuous sensory signals from orofacial skin and vical Spinal Cord and Caudal Medulla of the Rat. J Neurophysiol organs to the hypothalamus, and is involved in pain- 84:2078–2112 2560 Trigeminothalamic Tract Projections

8. Ray BS, Wolff HG (1940) Experimental Studies on Headache. the upper cervical spinal dorsal horn. The caudal portion Pain-Sensitive Structures of the Head and their Significance in of the subnucleus caudalis is analogous to the spinal Headache. Arch Surg 41:813–856 9. Sessle BJ (1987) The Neurobiology of Facial and Dental Pain: dorsal horn both histologically and physiologically. The Present Knowledge, Future Directions. J Dent Res 66:617–626 Rexed classification of the dorsal horn can be applied 10. Swanson LW (1987) The Hypothalamus. In: Hökfelt T and Swan- to its outer layers. Thus, the subnucleus caudalis is son LW (eds) Handbook of Chemical Neuroanatomy, vol 5, Inte- regarded as a laminated structure, and is sometimes re- grated Systems of the CNS, Part I. Elsevier, Amsterdam, pp 1–124 ferred to as the  medullary dorsal horn. After entering the central nervous system at the middle of the pons, small-diameter primary afferent (nociceptive) fibers Trigeminothalamic Tract Projections in the trigeminal nerve turn caudally, then descend in the spinal trigeminal tract, and finally terminate in the KE REN subnucleus caudalis. Nociceptive neurons, both noci- Department of Biomedical Sciences, University of ceptive specific and wide dynamic range types, can be Maryland, Baltimore, MD, USA recorded from the subnucleus caudalis. The thalamic- [email protected] projecting axons of subnucleus caudalis neurons carry pain and temperature information to the thalamus. Synonyms The subnucleus interpolaris appears gradually from Tractus Trigeminothalamicus; Lemnicus Trigeminalis a transition region at the level of the obex, where the subnuclei caudalis and interpolaris coexist in the same Definition transverse plane for a small distance (the  trigeminal The axon bundles of the secondary sensory neurons in Vi/Vc transition zone). The subnucleus interpolaris the spinal trigeminal nucleus and principal sensory nu- neurons have a well-defined and extensive projection to cleus of the  trigeminal nerve, which carry somatosen- the medial ventroposterior thalamic nucleus (VPM, the sory information fromthe headandface andterminate in medial part of the ventrobasal complex) (Phelan and theventralposteriorpartoftheoppositethalamus.Asthe Falls 1991). Nociceptive thalamic projecting neurons counterpart of the spinothalamictract, the trigeminotha- have been identified in subnucleus interpolaris. How- lamic axons from the spinal trigeminal nucleus, mainly ever, most thalamic projecting subnucleus interpolaris the subnucleus caudalis, convey nociceptive input. The neurons respond to deflection of mystacial vibrissae trigeminothalamic axons from the principal sensory nu- and are low-threshold mechanoreceptive (Jacquin et cleus, equivalent to the medial  lemniscal fibers,trans- al. 1986; Hayashi et al. 1984). Two types of thalamic mit discriminative tactile as well as proprioceptive im- ascending fibers have been identified in the subnucleus pulses. interpolaris:fast-conductingthickfibersterminateinthe posterior nucleus of the thalamus, and slow-conducting Characteristics thin fibers project to VPM (Veinante et al. 2000). The somesthetic information from orofacial regions is The subnucleus oralis is the most rostral subnucleus conveyedviathefifthcranialnerve,thetrigeminalnerve, of the spinal trigeminal nucleus. Fukushima and Kerr to the two major trigeminal sensory nuclei, the spinal (1979) found that the subnucleus oralis had no projec- trigeminal and the principal sensory nuclei. Populations tions to the thalamus in the rat. Using fluorescent dye of neurons in the trigeminal sensory nuclei then send tracers, however, subnucleus oralis neurons have been their axons to the thalamus via trigeminothalamic pro- shown to project to the thalamus in rodents (Bruce et jections.Thepatternandfunctionsoftrigeminothalamic al. 1987). The neurons of the subnucleus oralis may projections are specifically related to the individual sub- project to the contralateral thalamus via a relay in the nuclei of the spinal trigeminal nucleus and the thalamus juxtatrigeminal nucleus and principal sensory nucleus (FukushimaandKerr1979;RausellandJones1991).For (Zhang and Yang 1999). the purpose of completeness, the following discussion Principal Sensory Nucleus of the Trigeminal Nerve, Trigeminal will go beyond the projection to the ventrobasal thala- Nucleus Principalis mus, to also include trigeminal projections to other nu- clei of the thalamus that are related to pain processing. The principal sensory nucleus (main sensory nucleus) can be traced caudally to the level of the rostral tip of Spinal Trigeminal Nucleus the facial nucleus and contiguous obliquely with sub- The spinal trigeminal nucleus is further divided rostro- nucleus oralis. The principal sensory nucleus mainly re- caudally into the subnuclei oralis, interpolaris and cau- ceives large-diameter primary afferents and contributes dalis. Cytoarchitecturally, the general classification of to discriminative sensations. In the rat, the principal sen- the subnuclei for humans is applicable to lower animals sorynucleusthalamicprojectingaxonsarisefromsmall- such as the rat. and medium-sized neurons; large neurons (20–42 μm) The subnucleus caudalis appears at approximately the of the principal sensory nucleus do not project to the tha- level of the obex and continues caudally to merge with lamus (Fukushima and Kerr 1979). The ascending fibers Trigeminothalamic Tract Projections 2561 from the ventral and dorsal principal sensory nucleus project to the contralateral and ipsilateral VPM, respec- tively.

Subnuclei of the Thalamus The ascending trigeminal projections terminate in sev- eral thalamic subnuclei including the VPM, posterior thalamic nucleus, nucleus submedius and intralaminar nuclei centralis medialis and lateralis and parafas- cicular nucleus. The principal sensory nucleus and spinal trigeminal nucleus have complementary pro- jection foci in the thalamus (Rausell and Jones 1991, Williams et al. 1994). The principal sensory nucleus input enters the barreloid portion of VPM that contains  parvalbumin-immunoreactive cells. The ascend- ing fibers from spinal trigeminal nucleus terminate in non-barreloid VPM, which contains another calcium- binding protein,  calbindin-D28k. Calbindin D-28k and parvalbumin belong to calcium binding protein families and can be used as selective neural markers of central neurons. The trigeminal inputs to the posterior thalamic nucleus are mainly from the principal sensory nucleus and subnucleus interpolaris (Waite and Tracey 1995). The parafascicular nucleus of the thalamus re- ceives input from subnuclei caudalis and interpolaris, but not from principal sensory nucleus and subnucleus oralis (Krout et al. 2002). The nucleus submedius re- ceives a major input from the Vi/Vc transition zone, as well as from the subnucleus caudalis (Yoshida et al. Trigeminothalamic Tract Projections, Figure 1 Major thalamic projec- 1991, Craig and Dostrovsky 2001). tions from the trigeminal sensory nuclei. Sensory inputs from the head and face are relayed in the trigeminal brain stem nuclear complex, including Most trigeminothalamic projections are contralateral, the principal sensory nucleus (PrV) and spinal trigeminal nucleus (SpV). except that the subnucleus caudalis projects to bilateral The spinal trigeminal nucleus is further divided into subnuclei oralis (Vo),  intralaminar thalamic nuclei (Peschanski 1984), and interpolaris (Vi) and caudalis (Vc). The most caudal subnucleus interpo- laris and rostral caudalis merge to form a transition zone (Vi/Vc) at the the principal sensory nucleus has an ipsilateral pro- obex level. Large-diameter myelinated primary afferents mainly synapse jection to VPM (Fukushima and Kerr 1979) (Fig. 1). in the principal sensory nucleus, and small-diameter A-delta and C-fibers Although the major trigeminothalamic projections are travel caudally to terminate in the subnucleus caudalis. Neurons in the the inputs to VPM and posterior thalamic nucleus from spinal trigeminal nucleus, primarily the subnucleus caudalis, project to T contralateral medial ventroposterior nucleus of the thalamus (VPM), pos- the principal sensory nucleus and subnucleus interpo- terior thalamic nucleus (not shown), as well as bilateral intralaminar nuclei laris (Waite and Tracey 1995), they are generally not (ILN) and nucleus submedius (Sm). The trigeminal projection to the sub- concerned with nociceptive transmission, or at least medius is predominantly contralateral. The principal sensory nucleus and do not play a major role. Most VPM neurons relay the subnucleus caudalis project to the barreloid and non-barreloid regions (open circles in VPM) of the VPM, respectively. Note that discriminative and precisely organized tactile information from the face affective components of pain may be relayed by distinct pathways. Dashed and mouth. Neurons in the posterior nucleus and medial lines indicate transmission of discriminative tactile information from the thalamus including nucleus submedius, intralaminar head and face. nuclei and parafascicular nucleus are less somatotopi- cally organized in relaying sensory information than is nuclei interpolaris and oralis are also involved in the the VPM nucleus. orofacial pain process, although limited information is available on their ascending thalamic projections Trigeminothalamic Projection and Pain related to pain. One characteristic of the nociceptive Trigeminothalamic neurons are involved in transmit- trigeminothalamic projection is that a relatively small ting pain information from the craniofacial region. The number of nociceptive neurons in the subnucleus cau- trigeminothalamic projection involved in pain is mainly dalis projects to the VPM. This is in sharp contrast with from the subnucleus caudalis, where small-diameter the principal sensory nucleus, where a vast majority trigeminal primary afferents terminate. Specifically, of cells are connected to VPM. However, nociceptive neurons in the marginal layer (lamina I) of the subnu- trigeminothalamic neurons also project to the posterior cleus caudalis project to VPM and posterior thalamic thalamic nucleus, nucleus submedius and intralaminar nucleus (Shigenaga et al. 1979). Neurons in the sub- thalamic nuclei. 2562 Trigeminovascular System

Most lamina I trigeminothalamic nociceptive neu- 3. Fukushima T, Kerr FW (1979) Organization of Trigeminothala- rons in the subnucleus caudalis project to nucleus mic Tracts and Other Thalamic Afferent Systems of the Brain- stem in the Rat: Presence of Gelatinosa Neurons with Thalamic submedius, but not VPM. In contrast, most thermore- Connections. J Comp Neurol 183: 169–184 ceptive trigeminothalamic cells project to VPM (Craig 4. Hayashi H, Sumino R, Sessle BJ (1984) Functional Organization and Dostrovsky 2001). Subnucleus caudalis nocicep- of Trigeminal Subnucleus Interpolaris: Nociceptive and Innocu- tive neurons are antidromically activated by stimulation ous Afferent Inputs, Projections to Thalamus, Cerebellum, and Spinal Cord, and Descending Modulation from Periaqueductal of the posterior nucleus of the thalamus (Hirata et al. Gray. J Neurophysiol 51:890–905 1999). 5. Hendry SH, Hsiao SS (2003) The Somatosensory System, In: Using combined retrograde tracing and nuclear Fos pro- Squire LR, Bloom FE, McConnell SK, Roberts JL, Spitzer NC, tein expression techniques, it has been shown that a pop- Zigmond MJ (eds) Fundamental neuroscience. 2nd ed. Academic Press, London, pp 667–697 ulation of nucleus submedius-projecting neurons in the 6. Hirata H, Hu JW, Bereiter DA (1999) Responses of Medullary Vi/Vc transition zone isactivated by inflammation of the Dorsal Horn Neurons to Corneal Stimulation by CO2 Pulses in masseter muscle (Ikeda et al. 2003). In contrast, corneal the Rat. J Neurophysiol 82:2092–2107 responsive units in the Vi/Vc transition zone do not ap- 7. Ikeda T, Terayama R, Jue SS et al. (2003) Differential Rostral Projections of Caudal Brainstem Neurons receiving Trigeminal pear to project to the nucleus submedius (Hirata et al. Input after Masseter Inflammation. J Comp Neurol 465:220–233 1999).Thus,theVi/Vc-submediusprojectionmaybese- 8. Jacquin MF, Mooney RD, Rhoades RW (1986) Morphology, Re- lectively activated by injury of deep orofacial structures. sponse Properties, and Collateral Projections of Trigeminotha- The trigeminal nociceptive input to the VPM is further lamic Neurons in Brainstem Subnucleus Interpolaris of Rat. Exp Brain Res 61:457–468 relayed to the somatosensory cerebral cortex and related 9. Krout KE, Belzer RE, Loewy AD (2002) Brainstem Projections to discriminative information of pain. In contrast, infor- to Midline and Intralaminar Thalamic Nuclei of the Rat. J Comp mation about affective and emotional aspects of pain Neurol 448:53–101 10. Peschanski M (1984) Trigeminal Afferents to the Diencephalon from the head and face is likely to be related through in the Rat. Neuroscience 12:465–487 the thalamic nucleus submedius and intralaminar nuclei 11. Phelan KD, Falls WM (1991) A Comparison of the Distribution (Fig. 1). and Morphology of Thalamic, Cerebellar and Spinal Projection Neurons in Rat Trigeminal Nucleus Interpolaris. Neuroscience Trigeminothalamic Projection and Discriminative Sensations 40:497–511 Information related to discriminative sensations from 12. Rausell E, Jones EG (1991) Chemically Distinct Compartments of the Thalamic VPM Nucleus in Monkeys Relay Principal the head and face is relayed in the VPM through and Spinal Trigeminal Pathways to Different Layers of the trigeminothalamic projections. Neurons in the principal Somatosensory Cortex. J Neurosci 11:226–237 sensory nucleus receive synaptic contact from large- 13. Shigenaga Y, Takabatake M, Sugimoto T et al. (1979) Neurons in Marginal Layer of Trigeminal Nucleus Caudalis Projecting to diameter primary afferent terminals of the trigeminal Ventrobasal Complex (VB) and Posterior Nuclear Group (PO) nerve and send axons ascending to VPM. This pathway Demonstrated by Retrograde Labeling with Horseradish Perox- corresponds to the spinal dorsal column/medial lem- idase. Brain Res 166:391–396 niscal system, and is highly somatotopically organized. 14. Veinante P, Jacquin MF, Deschenes M (2000) Thalamic Projec- tions from the Whisker-Sensitive Regions of the Spinal Trigem- In rodents, distinct clusters of VPM cells receive inputs inal Complex in the Rat. J Comp Neurol 420: 233–243 from designated whiskers, mediated by corresponding 15. Waite Phil ME, Tracey DJ (1995) Trigeminal Sensory System. aggregates of neurons in the principal sensory nucleus. In: Paxinos G (ed) The rat nervous system, 2nd edn. Academic Neurons in the principal sensory nucleus, VPM and Press, San Diego, pp 705–724 16. Williams MN, Zahm DS, Jacquin MF (1994) Differential Foci the somatosensory cortex are grouped into rows (rods, and Synaptic Organization of the Principal and Spinal Trigeminal cellular cylinders) to give topographical representa- Projections to the Thalamus in the Rat. Eur J Neurosci 6:429–453 tion of the whisker pad. This specific array of cells is 17. Yoshida AK, Dostrovsky JO, Sessle BJ et al. (1991) Trigeminal named “barrels” in cortex, “barreloids” in VPM and Projections to the Nucleus Submedius of the Thalamus in the Rat. J Comp Neurol 307:609–625 “barrelets” in the principal sensory nucleus (Waite and 18. Zhang JD, Yang XL (1999) Projections from Subnucleus Oralis Tracey 1995; Hendry and Hsiao 2003). Information of the Spinal Trigeminal Nucleus to Contralateral Thalamus via related to discriminative pain from the head and face the Relay of Juxtatrigeminal Nucleus and Dorsomedial Part of the Principal Sensory Trigeminal Nucleus in the Rat. J Hirnforsch is relayed in the non-barreloid thalamic regions of the 39:301–310 VPM, complementary to those mediating tactile sensa- tions, or the barreloid areas (Rausell and Jones 1991; Williams et al. 1994). Trigeminovascular System

References Definition 1. Bruce LL, McHaffie JG, Stein BE (1987) The Organization of Trigeminotectal and Trigeminothalamic Neurons in Rodents: A The trigeminovascular system designates the visceral st Double-Labeling Study with Fluorescent Dyes. J Comp Neurol terminals of the 1 division of the trigeminal nerve 262: 315–330 surrounding vessels in the meninges. It is the major 2. Craig AD, Dostrovsky JO (2001) Differential Projections of pain-signaling structure of the visceral organ brain. Thermoreceptive and Nociceptive Lamina I Trigeminothalamic  and Spinothalamic Neurons in the Cat. J Neurophysiol 86: Clinical Migraine without Aura 856–870  Migraine, Pathophysiology TrkA Receptor(s) 2563

in neighboring skin areas due to axon reflex activation. Trigger Point Histamine activates nociceptive, unmyelinated C-fibers at the injection site. Their impulses travel orthodromi- Definition cally. As soon as they have reached axon branching A trigger point is a spot of localized tenderness in a pal- points, impulses also propagate antidromically down pable taut band of muscle. Pressure stimulation or pal- other neighboring branches of the sensory nerve fibers. pation on trigger points evoke a characteristic pattern of The antidromic impulses reach axon terminals and referredpainandtypicallyalocaltwitchresponse.There induce release of vasodilating and itching neuropep- are also scar, skin, and connective tissue sensitive spots tides, such as calcitonine gene related peptide (CGRP) that, when stimulated, mechanically refer pain and are or substance P, which also causes fluid extravasation sometimes called trigger points. (Ganong WF (1997) Review of Medical Physiology.  Chronic Pelvic Pain, Musculoskeletal Syndromes Appleton & Lange; Stamford, CT p581-582).  Muscle Pain, Fibromyalgia Syndrome (Primary, Sec-  Congenital Insensitivity to Pain with Anhidrosis ondary)  Myofascial Trigger Points  Psychophysiological Assessment of Pain  Referred Muscle Pain, Assessment  Stretching Triptans

Definition Trigger Point Pain Serotonin, 5–HT1B/1D, receptor agonist, i.e. compounds that activate or turn on both these receptor sub-types.  Myofascial Pain These compounds are highly effective in the treatment of acute migraine.  Clinical Migraine without Aura Trigger Point Pressure Release  Migraine, Pathophysiology

Definition Trigger point pressure release is a simple, often effec- tive, manual technique for the treatment of myofascial triggerpoints.Slowlyincreasing,gentle,digitalpressure trkA is applied to the trigger point until a barrier of tissue re- sistance isencountered. Constantpressure ismaintained  untilthe resistance of the barrier tensiondecreases. Then Tyrosine Kinase A pressure is slowly increased to reach a new barrier. The T term ischemic compression has previously been used to describe this treatment approach, but a different concept of the treatment mechanism was attributed to it, and the procedure was unnecessarily painful. TrkA Receptor(s)  Myofascial Trigger Points Definition Triple Response TrkA is a member of the trk family of tyrosine kinase re- ceptors and is the high affinity receptor for nerve growth factor found on NGF-dependentsensoryneurons. When Definition trkA binds NGF, the receptor autophosphorylateson ty- The triple response consists of three components. In rosine residues, leading to activation of multiple down- response to an intradermal histamine injection, there stream effector proteins, including the Ras-MAP kinase is a local erythema (reddening reaction) occurring signaling cascade and PI3–kinase activation. within 10 seconds due to a direct histamine induced  Congenital Insensitivity to Pain with Anhidrosis capillary dilatation at the injection site. Then, there is  IB4-Positive Neurons, Role in Inflammatory Pain a local swelling, a „wheal“, due to locally increased  Immunocytochemistry of Nociceptors permeability of capillaries and postcapillary venules  Nerve Growth Factor, Sensitizing ActiononNocicep- with consecutive fluid extravasation. Finally, there is a tors „flare“, i.e. an erythema occurring within 30 seconds  TRPV1, Regulation by Nerve Growth Factor 2564 TrkA-IgG

as receptors for temperature and irritant chemicals (cap- TrkA-IgG saicin, mustard oil) in the pain pathway, and play impor- tantfunctionalrolesin neurogenicinflammation and hy- Definition peralgesia.  NGF sequestering molecule. Nociceptors, Cold Thermotransduction   Spinal Cord Nociception, Neurotrophins TRPV1, Regulation by Nerve Growth Factor  TRPV1, Regulation by Protons

TRN TRPA1

 Thalamic Reticular Nucleus Definition Temperature-sensitive, non-selective cation channel ac- tivated near 17˚C. The channel is insensitive to menthol Trochanteric Bursitis but is activated by natural pungent compounds like cin- namon and mustard oil. The transcripts are expressed Definition in a small percentage (4%) of primary sensory neurons. Inflammation of the bursa near the greater trochanter of Found exclusively in neurons expressing TRPV1 and the hip. This condition can produce pain in the thigh. peptidergic markers of nociceptors, such as calcitonin  Sciatica gene-related peptide (CGRP). Suggested as the molec- ular transducer of noxious cold temperatures.  Nociceptors, Cold Thermotransduction Trophic Factors TRPM8 Channel Definition Molecules that cause growth/regeneration of various Definition parts of a cell/neuron; more recently some trophic Calcium permeable, voltage-gated, non-selective cation factors have also been shown to have transmitter-like channelthatisactivatedbytemperature(threshold25˚C) actions. and natural cooling compounds like menthol and euca-  Retrograde Cellular Changes after Nerve Injury lyptol.Expressedinaround10%ofprimarysensoryneu- ronsofsmalldiameter.Acrucialelementinthetransduc- tion of temperature signals by low-threshold peripheral Tropism and visceral thermoreceptors.  Nociceptors, Cold Thermotransduction Definition Movement or growth of an organism in response to an external stimulus. TRPV1  Hansen’s Disease Synonyms Transient Receptor Potential Vanilloid Type 1 TRP Channels Definition The TRPV1 receptor is a member of the transient recep- Definition tor vanilloid subfamily. It is sensitive to capsaicin and Denominatesion channelsof theTransientReceptorPo- has a well defined temperature threshold of about 43˚C, tential (TRP) family. The first member of this ion chan- similar to the threshold for thermal nociception. The re- nel family was identified by localization of a gene that sponse of this receptor can be sensitized to NGF and caused deficiencies in signaling in the visual system of other proinflammatory mediators providing a basis for themodelorganismDrosophilamelanogaster(fruitfly). thermal hyperalgesia. Other TRP subfamily members Mammals have more than 14 TRP channel genes. TRP are not sensitive to capsaicin, and have different temper- channels play important roles in the regulation of neural ature thresholds (e.g. TRPV2 – 52˚C;TRPV3–35˚C). excitability and in sensory systems, such as vision, ol- Still other members of this subfamily appear to respond faction, and pheromone sensation. TRP channels serve to other stimuli, e.g. TRPV4 – osmoreceptors. TRPV1 TRPV1 Modulation by p2Y Receptors 2565 is the charter member of a family of TRP channels iden- expression-cloning method and the receptor protein tified in mammalian sensory neurons that are activated was found to be an ion channel with six transmembrane by temperatures ranging from cold to warm to intense domains having high Ca2+ permeability (Caterina et al. heat. 1997). When expressed in heterologous systems, the  Capsaicin Receptor cloned capsaicin receptor TRPV1 can also be activated  ERK Regulation in Sensory Neurons during Inflam- by noxious heat (with a thermal threshold > 43˚C) or mation protons (acidification), both of which cause pain in  IB4-Positive Neurons, Role in Inflammatory Pain vivo (Caterina et al. 1997; Tominaga et al. 1998; Cate-  Muscle Pain Model, Ischemia-Induced and Hyper- rina and Julius 2001). Furthermore, analyses of mice tonic Saline-Induced lacking TRPV1 have shown that TRPV1 is essential  Nerve Growth Factor, SensitizingActiononNocicep- for selective modalities of pain sensation and for tissue tors injury-induced thermal hyperalgesia (Caterina et al.  NGF, Regulation during Inflammation 2000; Davis et al. 2000).  Nociceptor, Categorization Tissue damage associated with infection, inflammation  Satellite Cells and Inflammatory Pain or ischemia produces an array of chemical mediators  Species Differences in Skin Nociception that activate or sensitize nociceptor terminals to elicit  TRPV1 Modulation by p2Y Receptors pain at the site of injury. One important component  TRPV1 Receptor, Species Variability of this pro-algesic response is adenosine triphosphate  TRPV1, Regulation by Nerve Growth Factor (ATP) released from different cell types (North and  TRPV1, Regulation by Protons Barnard 1997; Burnstock and Williams 2000). Extra-  Visceral Pain Model, Esophageal Pain cellular ATP excites the nociceptive endings of nearby sensory nerves, evoking a sensation of pain. In these neurons, the most widely studied targets of extracellu- lar ATP have been ionotropic ATP  (P2X) receptors. TRPV1 Modulation by p2Y Receptors Indeed, several P2X receptor subtypes have been iden- tified in sensory neurons, including one (P2X3) whose MAKOTO TOMINAGA expression is largely confined to these cells (North and Department of Cellular and Molecular Physiology, Barnard 1997). The importance of widely distributed Mie University School of Medicine, Tsu Mie, Japan metabotropic ATP (P2Y) receptors in nociception has [email protected] been recently reported (Molliver et al. 2002; Zimmer- mannetal.2002).Inparticular,thefunctionalinteraction Synonyms between P2Y receptors and TRPV1 has received much TRPV1 Receptor, Modulation by P2Y Receptors attention because TRPV1 is one of the key molecules detecting nociceptive stimuli and because the signaling Definition pathway downstream of P2Y receptor activation can be applicable for other G -protein coupled receptor   q Capsaicin receptor TRPV1 is a non-selective activation. T cation channel expressed in a subset of sensory neurons, Pretreatment with 100 μM extracellular ATP (an at-   nociceptors. P2Y receptor activation potentiates or tainable concentration in the context of tissue damage)  sensitizes TRPV1 activity through a PKC-dependent causes more than 6 times the potentiation of capsaicin  pathway. In the presence of ATP released in the (low doses)-evoked current responses in HEK293 cells context of tissue damage, the temperature threshold heterologously expressing TRPV1 channels (Fig. 1a) for TRPV1 activation is reduced to less than 35˚C, so (Tominaga et al. 2001). A similar potentiating effect of that body temperature is capable of activating TRPV1, extracellular ATP is observed on proton-evoked activa- leading to the sensation of pain. tion of TRPV1. The dose-response curves for capsaicin in the presence or absence of ATP demonstrate that Characteristics ATP enhances capsaicin and proton action on TRPV1 Pain is initiated when noxious thermal, mechanical, or by lowering  EC50 values without altering maximal chemical stimuli excite the peripheral terminals of spe- responses (Fig. 1b). Extracellular ATP also lowers the cialized primary afferent neurons called nociceptors. threshold temperature for TRPV1 activation signifi- Many different kinds of ionotropic and metabotropic cantly (from about 43˚C to about 35˚C) (Fig. 1c). Thus, receptors are known to be involved in this process in the presence of ATP, normally non-painful thermal (McCleskey and Gold 1999).  Vanilloid receptors are stimuli (even body temperature) are capable of acti- nociceptor-specific cation channels that serve as the vating TRPV1. These data show that TRPV1 currents molecular target of capsaicin, the pungent ingredient in evoked by any of three different stimuli (capsaicin, hot chili peppers (Szallasi and Blumberg 1999). A gene proton or heat) are potentiated or sensitized by extra- encoding a capsaicin receptor was isolated using an cellular ATP. Activation of protein kinase C (PKC) by 2566 TRPV1 Modulation by p2Y Receptors

TRPV1 Modulation by p2Y Receptors, Figure 1 (a) Extracellular ATP (100 μM) potentiates capsaicin (CAP)-activated currents in HEK293 cells expressing TRPV1. Whole-cell patch-clamp recordings were carried out with holding potential of -60 mV. Cells were perfused for 2 min with solution containing ATP before re-exposure to capsaicin. (b) Capsaicin dose-response curves for TRPV1 in the absence (λ) and presence (μ) of 100 μM extracellular ATP. Currents were normalized to the currents maximally activated by 1 μM capsaicin in the absence of ATP. Figure shows averaged data fitted with the Hill equation. EC50 = 114.7 nM and Hill coefficient = 1.48 in the absence of ATP. EC50 = 49.3 nM and Hill coefficient = 1.56 in the presence of ATP. Values represent the mean ± SEM. (c) Reduction of the threshold temperature for TRPV1 activation by extracellular ATP. Representative temperature- response profiles in the absence and presence of 100 μM extracellular ATP. Dashed lines show the threshold temperature for heat activation of VR1. Temperature threshold for activation of TRPV1 in the presence of ATP (35.3 ± 0.7˚C) was significantly lower than that in the absence of ATP (41.7 ± 1.1˚C). *, p < 0.001 (Tominaga et al. 2001). diacylglycerol (DAG) downstream of P2Y1 receptors P2Y subtypes are involved in ATP-induced thermal is found to be a mechanism for the ATP-induced po- hyperalgesia in mice. tentiation from various pharmacological analyses in Electrophysiological and pharmacological analyses HEK293 cells (Fig. 2a), consistent with the report using DRG neurons of mice revealed that P2Y2 is that PKC- is specifically involved in sensitization of a subtype involved in ATP-induced potentiation of heat-activated channels by  bradykinin in dorsal root TRPV1 currents and ATP-induced thermal hyperal- ganglion (DRG) neurons. gesia in mice (Moriyama et al. 2003). UTP, a potent The interaction between ATP and TRPV1 in the con- P2Y2 receptor agonist, potentiates the capsaicin-evoked text of ATP-induced hyperalgesia in vivo is confirmed current responses and causes thermal hyperalgesia to a by a behavioral analysis using wild type mice and similar extent as ATP in mice, further confirming the 1- TRPV deficient mice (Moriyama et al. 2003). A sig- involvement of P2Y2 receptors. P2Y2 receptor mRNA nificant reduction in paw withdrawal latency to radiant but not P2Y1 mRNA is found to be co-expressed with paw heating is observed for 5 to 30 min following TRPV1 mRNA in the rat lumbar DRG using double ATP injection in wild type mice. On the other hand, in situ hybridization, suggesting that P2Y2, not P2Y1 TRPV1-deficient mice develop no such thermal hyper- receptors, can functionally interact with TRPV1 in sensitivity in response to ATP injection, suggesting a DRG neurons functional interaction between ATP and TRPV1 (Fig. The data described above suggest that direct phosphory- 2b). Mice lacking P2Y1 receptors, a subtype proved lation of TRPV1 or a closely associated protein by PKC to be involved in ATP-induced potentiation of TRPV1 changes the agonist sensitivity of this ion channel. The currents in HEK293 cells, showed similar thermal in vivo phosphorylation of TRPV1 by PKC is confirmed hyperalgesia to wild type mice, indicating that other in HEK293 cells expressing TRPV1 (Numazaki et al. TRPV1 Modulation by p2Y Receptors 2567

TRPV1 Modulation by p2Y Receptors, Figure 2 (a) Regulation mechanisms of TRPV1 by P2Y receptors. Gq-coupled P2Y receptor activation leads to production of IP3 and DAG through PLCβ. PKC activation by DAG causes phosphorylation of TRPV1, leading to functional potentiation. PLCβ, phospholipase Cβ; DAG, diacylglycerol; IP3, inositol 1,4,5-trisphosphate; P, phosphorylation; o and I, outside and inside of cell, respectively. (b) TRPV1 is essential for the development of ATP-induced thermal hypersensitivity in vivo. Wild type (γ)orTRPV1 -/- mice (γ) were injected intraplantarly with ATP (100 nmol), and the response latency to radiant heating of the hind paw was measured at various time points after injection. * p < 0.05 and ** p < 0.01 vs. wild type mice. (Moriyama et al. 2003).

2002).Furthermore,twoserineresiduesassubstratesfor making ATP act like a direct activator of TRPV1. This PKC-dependent phosphorylation, S502 in thefirst intra- represents a novel mechanism through which extracel- cellular loop and S800 inthe C-terminus, wereidentified lular ATP may cause inflammatory pain. Most attention using an in vitro kinase assay (Numazaki et al. 2002). A in the pain field has focused on the role of ionotropic mutant lacking substrates for PKC-dependent phospho- ATP receptors in ATP-evoked nociception. The above T rylation (S502A/S800A) exhibited almost no potentia- findings suggest that P2Y2 is also involved in this pro- tion effects of capsaicin- or proton-evoked current re- cess and may represent a fruitful target for the develop- sponses by PMA (a direct activator of PKC). Further- ment of drugs that blunt nociceptive signaling through more, the double mutant showed no reduction in tem- capsaicin receptors. P2Y2 receptors confer responsive- peraturethresholdforTRPV1activation,suggestingthat ness to uridine triphosphate (UTP) and ATP to a simi- the two serine residuesare the major substratesfor PKC- lar extent, suggesting a possible role for UTP as an im- dependent phosphorylation. portant component of pro-algesic response in the con- Inflammatory pain is initiated by tissue damage/inflam- text of tissue injury. UTP was indeed found to potentiate mation and is characterized by hypersensitivity both at capsaicin-activated currents and cause thermal hyperal- the site of damage and in adjacent tissue. One mech- gesia in mice (Moriyama et al. 2003). anism underlying these phenomena is the modulation These results suggest that activation of similar PKC- (sensitization) of ion channels, such as TRPV1, that de- dependent events might underlie certain nociceptive tect noxious stimuli at the nociceptor terminal. Sensi- effects of other Gq-coupled metabotropic receptors. tization is triggered by extracellular inflammatory me- Indeed, bradykinin is found to potentiate or sensitize diators that are released in vivo from surrounding dam- TRPV1 in a similar PKC-dependent pathway through aged or inflamed tissue and from nociceptive neurons the activation of B2 receptors (Sugiura et al. 2002). themselves.Amongthemediators,ATPnotonlypotenti- atescapsaicin-orproton-evokedcurrentsbutalsolowers References the temperature threshold for heat activation of TRPV1, 1. Burnstock G, Williams M (2000) P2 purinergic receptors: mod- such that normally non-painful thermal stimuli (i.e. nor- ulation of cell function and therapeutic potential. J Pharmacol malbodytemperature)arecapableofactivatingTRPV1, Exp Ther 295:862–869 2568 TRPV1 Modulation by PKC

2. Caterina MJ, Schumacher MA, Tominaga M et al. (1997) The so the nerve terminal becomes hyperalgesic (hypersen- capsaicin receptor: a heat-activated ion channel in the pain path- sitive to heat pain). Many inflammatory mediators act way. Nature 389:816–824 3. Caterina MJ, Leffler A, Malmberg AB et al. (2000) Impaired by stimulating an intracellular enzyme known as pro- nociception and pain sensation in mice lacking the capsaicin re- tein kinase C (a member of the large kinase family of ceptor. Science 288:306–313 enzymes), which attach phosphate groups to specific 4. Caterina MJ, Julius D (2001) The vanilloid receptor: a molecular locations on the portion of the TRPV1 protein exposed gateway to the pain pathway. Annu Rev Neurosci 24:487–517 5. Davis, J.B., Gray, J., Gunthorpe, M.J et al. (2000) Vanilloid to the intracellular milieu of the nociceptor terminal. receptor-1 is essential for inflammatory thermal hyperalgesia. Nature 405:183–187 Characteristics 6. McCleskey EW, Gold MS (1999) Ion channels of nociception. Annu Rev Physiol 61:835–856 A role for PKC in nociceptor sensitization was first 7. Molliver DC, Cook SP,Carlsten JA et al. (2002) ATP and UTP ex- suspected in studies of the potent sensitizing agent cite sensory neurons and induce CREB phosphorylation through bradykinin, a pro-inflammatory nonapeptide which is the metabotropic receptor, P2Y2. Eur J Neurosci 16:1850–1860 released from a larger precursor protein by proteolytic 8. Moriyama T, Iida T, Kobayashi K et al. (2003) Possible involve- cleavage following tissue damage (Dray and Perkins ment of P2Y2 metabotropic receptors in ATP-induced transient receptor potential vanilloid receptor 1-mediated thermal hyper- 1993). Bradykinin is one of the most potent pain- sensitivity. J Neurosci 23:6058–6062 producing substances known, and as well as causing 9. North AN, Barnard EA (1997) Nucleotide receptors. Curr Opin pain directly, it acts as a sensitising agent which lowers Neurobiol 7:346–357 10. Numazaki M, Tominaga T, Toyooka H et al. (2002) Direct phos- the temperature threshold for the activation of heat pain phorylation of capsaicin receptor VR1 by PKC and identification of two target serine residues. J Biol Chem 277:13375–13378 11. Sugiura T, Tominaga M, Katsuya H et al. (2002) Bradykinin lowers the threshold temperature for heat activation of vanilloid receptor 1. J Neurophysiol 88:544–548 12. Szallasi A, Blumberg PM (1999) Vanilloid (capsaicin) receptors and mechanisms. Pharmacol Rev 51:159–211 13. Tominaga M, Caterina MJ, Malmberg AB et al. (1998) The cloned capsaicin receptor integrates multiple pain-producing stimuli. Neuron 21:531–543 14. Tominaga M, Wada M, Masu M (2001) Potentiation of capsaicin receptor activity by metabotropic ATP receptors as a possible mechanism for ATP-evoked pain and hyperalgesia. Proc Natl Acad Sci USA 98:6951–6956 15. Zimmermann K, Reeh PW, Averbeck B (2002) ATP can en- hance the proton-induced CGRP release through P2Y receptors and secondary PGE(2) release in isolated rat dura mater. Pain 97:259–265

TRPV1 Modulation by PKC

PETER A. MCNAUGHTON Department of Pharmacology, University of Cambridge, Cambridge, UK [email protected]

Synonyms VR1; PKC; protein kinase C; TRPV1 Modulation by PKC Definition TRPV1 is an ion channel located in the surface mem- brane of pain-sensitive nerve terminals or nocicep- tors, which is activated by capsaicin, heat and protons. TRPV1 Modulation by PKC, Figure 1 Action potentials and generator TRPV1 when open conducts electric charge, in the form currents elicited in a nociceptive neuron by a noxious heat stimulus. (a) + 2+ Application of a 49˚C heat stimulus depolarizes a nociceptive neuron to of cations (mainly Na and Ca ) and therefore makes threshold and elicits a train of action potentials. This temperature did not the interior of the nociceptor more positive, leading damage the neuron as repeated application of the stimulus gave similar to the generation of action potentials. The temperature results. (b) Dependence of the membrane current on temperature in a heat- sensitive neuron before and after activation of PKC by phorbol myristate threshold of TRPV1 is lowered when inflammatory me- acetate (PMA), a PKC-specific activator. After activation of PKC the activation diators such as bradykinin or ATP interact with surface threshold shifts to lower temperatures and the magnitude of the current membrane receptors on nociceptive nerve terminals and increases. TRPV1 Modulation by PKC 2569

TRPV1 Modulation by PKC, Figure 2 Pathways leading to heat hyperalgesia. Binding of bradykinin to its receptor activates PLCβ,which in releases DAG from PIP2, leading to activation of PKCε,whichinturn phosphorylates TRPV1 at two serine residues, leading to the lowering of heat threshold shown in Fig. 1b. in vivo (Mizumura and Kumazawa 1996). In isolated of individual serine or threonine residues, followed nociceptive neurons action potentials are elicited by by expression of the mutant TRPV1 in a heterologous heat stimuli (Fig. 1a), just as they are in vivo,andthe expression system (Numazaki et al. 2002). Mutation inward membrane current responsible can be recorded of two serines to alanine, which cannot be phosphory- using the whole-cell voltage clamp technique (Fig. 1b). lated, abolished sensitization following PKC activation The properties of the heat-gated ion current, such as (Fig. 2). The isoform of PKC responsible has also been its threshold and dependence on temperature, closely identified (Cesare et al. 1999). Of the eleven known correspond to those of heat pain in vivo (Cesare and isoforms of PKC only five, namely PKCβI, βII, δ,  McNaughton 1996). Bradykinin is a potent agonist at and ζ, are expressed to any significant extent in sen- the G-protein coupled B2 receptor, leading to activa- sory neurons and of these only PKC is translocated tion of Gq and phospholipase C β (PLCβ), followed to the membrane following exposure to bradykinin, by metabolism of phosphatidylinositol bisphosphate suggesting that it is this isoform which is responsible (PIP2) and release of diacylglycerol (DAG) and inositol for sensitization of TRPV1. A central role for PKC in trisphosphate (IP3). These two products have different sensitization was confirmed by showing that constitu-  actions: DAG activates protein kinase C (PKC) while tively active PKC incorporated into the cell was indeed T IP3 releases calcium from intracellular organelles. The capable of sensitising the heat-gated current, and that critical member of this cascade which is responsible for the incorporation of a specific PKC inhibitor into the causing sensitization of the heat-gated membrane cur- cell largely abolished sensitisation (Cesare et al. 1999). rentisPKC,becausethesensitisingeffectsofbradykinin A specific role for PKC in nociceptor sensitization is are mimicked by direct PKC activation (Fig. 1b), are also suggested by the reduced heat hyperalgesia seen in antagonized by PKC inhibitors such as staurosporine studies using PKC knockoutmice (Khasar et al. 1999). and are promoted by phosphatase inhibitors such as The model of specific phosphorylation of TRPV1 by calyculin A (Cesare and McNaughton 1996; Cesare PKC is shown in outline in Fig. 2. and McNaughton 1997). In an alternative model (Chuang et al. 2001) TRPV1 is TRPV1 is activated by heat stimuli, and is the molecule proposedtobetonicallyinhibitedbyPIP2intheneuronal responsible for the heat hyperalgesia caused by inflam- cell membrane. Removal of PIP2, when bradykinin ac- mation, because no heat hyperalgesia is seen in animals tivates PLCβ, is then proposed to release TRPV1 from from which TRPV1 has been genetically deleted (Davis inhibition. This model is supported by experiments et al. 2000; Caterina et al. 2000). Two main models have in which application of PLCβ to isolated membrane been proposed for the molecular basis of this hyperal- patches in order to break down PIP2, or removal of gesia. In experiments on isolated neurons (see above) PIP2 with an antibody, potentiated gating of TRPV1 PKC has been identified as a critical mediator of heat (Chuang et al. 2001). The proposal also draws on work hyperalgesia. PKC acts by phosphorylating serine or carried out on other ion channels, particularly on in- threonine residues on its target proteins and phosphory- ward rectifier potassium channels, where a modulation lation sites relevant for the process of sensitisation have of ion channel function by PIP2 is well established been identified by the use of site-directed mutagenesis (Hilgemann 2003). It has yet to be clearly established 2570 TRPV1 Modulation by PKC whether this mechanism plays an important role in TRPV1 sensitization, but the observations cited above TRPV1 Receptor, Modulation by P2Y suggest that it plays at most a minor role by comparison Receptors with the PKC pathway summarized in Fig. 2.  TRPV1 Modulation by p2Y Receptors References 1. Caterina MJ, Leffler A, Malmberget AB et al. (2000) Impaired nociception and pain sensation in mice lacking the capsaicin re- ceptor. Science 288:306–313 2. Cesare P, McNaughton PA (1996) A novel heat-activated current TRPV1 Receptor, Species Variability in nociceptive neurons, and its sensitization by bradykinin. Proc Natl Acad Sci USA 93:15435–15439 PETER MCINTYRE 3. Cesare P, McNaughton PA (1997) Peripheral pain mechanisms. Department of Pharmacology, University of Curr Opin Neurobiol 7:493–499 Melbourne, Melbourne, VIC, Australia 4. Cesare P, Dekker LV, Sardini A et al. (1999) Specific involve- ment of PKC-epsilon in sensitization of the neuronal response [email protected] to painful heat. Neuron 23:617–624 5. Chuang HH, Prescott ED, Kong H et al. (2001) Bradykinin and nerve growth factor release the capsaicin receptor from Synonyms PtdIns(4,5)P2-mediated inhibition. Nature 411:957–962 Transient receptor potential cation channel, subfamily 6. Davis JB, Gray J, Gunthorpe MJ et al. (2000) Vanilloid receptor- 1 is essential for inflammatory thermal hyperalgesia. Nature V,member 1; TRPV1; Capsaicin receptor; VanilloidRe- 405:183–187 ceptor Subtype 1; VR1 7. Dray A, Perkins M (1993) Bradykinin and inflammatory pain. Trends Neurosci 16:99–104 8. Hilgemann DW (2003) Getting ready for the decade of the lipids. Definition Annu Rev Physiol 65:697–700 TRPV1isanon-specificcationchannelofthe transient 9. Khasar SG, Lin Y-H, Martin A et al. (1999) A novel nociceptor signaling pathway revealed in protein kinase c epsilon mutant receptor potential protein family, which is expressed mice. Neuron 24:253–260 in  polymodal sensory neurons in the peripheral sen- 10. Mizumura K, Kumazawa T (1996) Modification of nociceptor sory nervous system and is activated by noxious heat responses by inflammatory mediators and second messengers (>43˚C), pH below 6.5, capsaicin, the pungent ingre- implicated in their action – A study in canine testicular polymodal receptors. Prog Brain Res 113:115–141 dient of chili peppers, resiniferatoxin and a number 11. Numazaki M, Tominaga T, Toyooka H et al. (2002) Direct phos- of other vanilloid, phorbol-related compounds as well phorylation of capsaicin receptor VR1 by protein kinase Cep- as the endogenous activators anandamide and some silon and identification of two target serine residues. J Biol Chem products of lipoxygenase action on arachidonic acid. 277:13375–13378 Characteristics Relatives of TRPV1 TRPV1 Modulation by PKC TRPV1 is a non-selective cation channel with high cal- cium permeability. It has a long cytoplasmic N-terminal tail with 3 ankyrin repeats and 6 hydrophobic domains  TRPV1 Modulation by PKC (termed S1–S6 here) which may be transmembrane do- mains and a putative pore-forming region between S5 and S6. It is a member of the superfamily of ion channels with six hydrophobic transmembrane domains and apu- TRPV1-Null Mice tativepore-formingloopbetweenthelasttwohydropho- bic domains. This superfamily includes the voltage acti- Definition vated potassium channels, hyperpolarization and cyclic nucleotide gated channels (HCN) and the transient re- Mice that have a disruption of the TRPV1 gene. These ceptor potential (TRP) ion channels, which are involved mice lack expression of the TRPV1 protein and have no in many sensory processes. response to capsaicin.  IB4-Positive Neurons, Role in Inflammatory Pain Splice Variants TRPV1 was first isolated by expression cloning from rat sensory neurons (Caterina et al. 1997) and has sub- sequently been isolated from human (McIntyre et al. TRPV1 Receptor 2001; Cortright et al. 2001; Hayes et al. 2000), guinea pig (Savidge et al. 2002), mouse (Accession number AJ620495), rabbit (Accession number AY487342) and  TRPV1 chicken (Jordt and Julius 2002) sources and partial se- TRPV1 Receptor, Species Variability 2571 quences are available from gene predictions from dog TRPV1 alleles both give rise to functional channels and zebrafish. Cloning and sequencing of the human with no reported differences in pharmacology (Hayes and mouse genes has shown that the trpv1 gene has 16 et al. 2000). exons in mouse and human predicted by Ensembl with 15 coding exons and that there are four splice variants of Protein Sequence Alignment mRNA. The TRPV1 gene is found at position 17p13.2 Alignment of the predicted proteins using Clustal W in the human genome and in a highly  syntenic region shows that the highest variation occurs at the N- and C- on chromosome 10 in the rat genome (Xue et al. 2001) terminal regions of the protein and within the putative and chromosome 11 in the mouse genome (Caterina pore region. Overall homology scores (Table 1) show et al. 2000). The predicted protein size is 839 amino thatratandmousesequenceshavemostidentity(94.9%) acids in human, guinea pig and mouse (~95 kD), 838 and that apart from these closely related sequences, the amino acids in rat, 842 in the rabbit and 843 (96.5 kD) mammalian proteins determined so-far share between in chicken. The rat protein can be glycosylated at as- 85.7% and 88.5% identity. The mammalian proteins paragine 604, migrateswith a higher apparentmolecular have between 64% and 66% identity to the chicken mass in its glycosylated form and can form tetramers protein. that are likely to be the functional form of the channel (Kedei et al. 2001). Pharmacological Differences An N-terminal splice variant, with most of the ankyrin Agonists domains and the cytoplasmic tail missing, has been The most extreme example of variation in pharmaco- observed (Schumacher et al. 2000b). The transcript logical characteristics of TRPV1 is between the rat and termed VR.5’sv is not functional but the protein is ex- chicken  orthologues. Primary sensory neurons from pressed in rat kidney and this splice variant is expressed chicks are responsive to heat (~45˚C) and low pH (pH 4) at low levels in dorsal root ganglia compared to TRPV1 but not capsaicin (Marin-Burgin et al. 2000). The cloned (Sanchez et al. 2001). The importance of this transcript, chicken TRPV1 has these properties when expressed in if any, is still not understood but it appears that an intact Xenopus oocytes or mammalian cells (Jordt and Julius N-terminus is essential for TRPV1 to be functional. 2002). Jordt and Julius showed, using chimeric recep- An earlier report of a TRPV1 transcript termed stretch- tors, that the molecular determinants for this difference inhibited channel (SIC) with differences at both C- layinsequencewithintheS3andS4regions;specifically and N-termini (Schumacher et al. 2000a) seems to be residues responsible for capsaicin sensitivity are tyro- derived from two independent genes and is unlikely to sine511andserine512,whereasarginine491wasshown be a functional TRPV1 transcript (Xue et al. 2001). to modulate the ratio of capsaicin-evoked current to pH- evoked current in electrophysiological experiments. Single Nucleotide Polymorphism Differencesinagonistsensitivityhavebeenfoundwithin One non-synonymous  single nucleotide polymor- TRPV1 from mammalian species. The rabbit TRPV1 is phism resulting in the amino acid substitution from unresponsive to capsaicin and substitution of threonine valine to isoleucine at position 585 has been reported in 553 for isoleucine is largely responsible for this phe- T the human TRPV1 sequence (Hayes et al. 2000). Geno- notype (Gavva et al. 2003). Rat TRPV1 responds well typing of DNA from 123 randomly selected, mixed to the agonist phorbol 12-phenylacetate 13-acetate 20- race individuals, showed that 51% of the population homovanillate (PPAHV) but the human (McIntyre et al. are heterozygous, the homozygous valine-encoding 2001) and guinea pig (Savidge et al. 2002) channels do allele occurs in 15% and the homozygous isoleucine- not. This difference has been mapped to a single con- encoding allele occurs in 34% of the population. These servative amino acid change. Mutation of leucine 457

TRPV1 Receptor, Species Variability, Table 1 TRPV1 percent amino acid identity (top triangle) and divergence (lower triangle) calculated using Clustal W rat mouse rabbit human guinea pig chicken

rat *** 94.9 86.9 85.7 88.0 65.8

mouse 5.1 *** 88.0 86.3 88.5 66.0

rabbit 14.2 13.0 *** 88.0 87.5 65.2

human 15.4 14.5 13.0 *** 86.5 64.0

guinea pig 12.6 12.3 13.6 14.3 *** 66.0

chicken 41.0 40.9 41.3 43.1 40.7 *** 2572 TRPV1 Receptor, Species Variability

TRPV1 Receptor, Species Variability, Figure 1 Alignment of the available predicted full-length proteins using Clustal W (DNAstar). Predicted ankyrin repeat regions are shaded grey and hydrophobic transmembrane domains are underlined and marked S1−S6. The most conserved regions are the hydrophobic domains which are thought to be buried in the membrane and the least conserved regions are the N-terminal and C-terminal regions and the proximal part of the putative pore region between S5 and S6. to methionine enables the human TRPV1 to respond to TRPV1. The residues responsible for this change were PPAHV (Phillips et al. 2004). mutated to the human equivalents and restored the phe- notype and thus the difference was mapped to amino acids isoleucine 514, valine 518 and methionine 547 in Antagonists the rat TRPV1. There is a pharmacological difference in the ability of In summary, severalgroupshave shownthatresiduesbe- capsazepine to antagonize the low pH and heat activa- tween hydrophobicdomains S2 and S4 are important in tion of the rat TRPV1 (McIntyre et al. 2001). Whereas recognition of agonists and antagonists and that small it blocks these modalities well in human and guinea pig variations in sequence can have significant effects on the TRPV1, it has little or no effect on these modalities in rat pharmacology of this ion channel. TRPV1 Receptor, Species Variability 2573

T

TRPV1 Receptor, Species Variability, Figure 1 (continued)

References 4. Gavva NR, Klionsky L, Qu Y et al. (2003) Molecular deter- minants of capsaicin sensitivity in rabbit TRPV1. Society for 1. Caterina MJ, Schumacher MA, Tominaga M et al. (1997) The Neuroscience Abstracts 811.12 capsaicin receptor: a heat-activated ion channel in the pain path- 5. Hayes P, Meadows HJ, Gunthorpe MJ et al. (2000) Cloning and way. Nature 389:816–824 functional expression of a human orthologue of rat vanilloid 2. Caterina MJ, Leffler A, Malmberg AB et al. (2000) Impaired receptor-1. Pain 88:205–215 nociception and pain sensation in mice lacking the capsaicin re- 6. Jordt SE, Julius D (2002) Molecular basis for species-specific ceptor. Science 288:306–313 sensitivity to “hot” chili peppers. Cell 108:421–430 3. Cortright DN, Crandall M, Sanchez JF et al. (2001) The tis- 7. Kedei N, Szabo T, Lile JD et al. (2001) Analysis of the na- sue distribution and functional characterization of human VR1. tive quaternary structure of vanilloid receptor 1. J Biol Chem Biochem Biophys Res Commun 281:1183–1189 276:28613–28619 2574 TRPV1, Regulation by Acid

8. Marin-Burgin A, Reppenhagen S, Klusch A et al. (2000) Low- Characteristics threshold heat response antagonized by capsazepine in chick sen- sory neurons, which are capsaicin-insensitive. Eur J Neurosci 12:3560–3566 Tissue damage produces a variety of mediators that ac- 9. McIntyre P, McLatchie LM, Chambers A et al. (2001) Pharmaco- tivate or sensitize nociceptor terminals and elicit pain. logical differences between the human and rat vanilloid receptor These mediators include peptides such as bradykinin or 1 (VR1). Br J Pharmacol 132:1084–1094 nerve growth factor (NGF) that bind to their receptors 10. Phillips E, Reeve A, Bevan S et al. (2004) Identification of species-specific determinants of the action of the antagonist on the nociceptor membrane and activate intracellular capsazepine and the agonist PPAHV on TRPV1. J Biol Chem signaling pathways that lead to neural activation or sen- 279:17165–17172 sitization. 11. Sanchez JF, Krause JE, Cortright DN (2001) The distribution and NGF is the prototypical member of the neurotrophin regulation of vanilloid receptor VR1 and VR1 5’ splice variant RNA expression in rat. Neuroscience 107:373–381 family. During mammalian development NGF is essen- 12. Savidge J, Davis C, Shah K et al. (2002) Cloning and func- tial for the survival of sensory neurons and contributes tional characterization of the guinea pig vanilloid receptor 1. to the maintenance of their phenotypes within the first Neuropharmacology 43:450–456 two weeks after birth. In the adult NGF is not required 13. Schumacher MA, Jong BE, FreySL et al. (2000a) The stretch- inactivated channel, a vanilloid receptor variant, is expressed for cell survival. in small-diameter sensory neurons in the rat. Neurosci Lett The NGF peptide consists of three subunits, alpha, beta 287:215–218 and gamma. The active neurotrophic peptide is the beta 14. Schumacher MA, Moff I, Sudanagunta SP et al. (2000b) Molecu- subunit that is processed by proteases and contains 118 lar cloning of an N-terminal splice variant of the capsaicin recep- tor. Loss of N-terminal domain suggests functional divergence amino acids. NGFbindsto a specific high-affinity recep- among capsaicin receptor subtypes. J Biol Chem 275:2756–2762 tor,  TrkA, on the cell membrane (Kaplan and Miller 15. Xue Q, Yu Y, Trilk SL et al. (2001) The genomic organization of 2000). TrkAbelongstothereceptortyrosinekinasefam- the gene encoding the vanilloid receptor: evidence for multiple splice variants. Genomics 76:14–20 ily of membrane receptors. Thispeptide receptor protein family has > 50 members and includes the receptors for other neurotrophinsandepidermalgrowth factor(EGF), platelet-derived growth factor (PDGF) and insulin. The TRPV1, Regulation by Acid TrkA protein consists of an extracellular ligand binding domain, a single transmembrane domain that transmits the extracellular signal and an intracellular domain that  TRPV1, Regulation by Protons is responsible for intracellular signaling and for the for- mation of a signaling complex with other proteins. While the role of NGF in the developing nervous sys- tem is firmly established, the concept of NGF as a no- TRPV1, Regulation by Nerve Growth ciceptive signaling molecule is relatively new. NGF has Factor beenshowntocontributetoinflammationandinflamma- tory pain in numerous studies. During injury and inflam- SVEN-ERIC JORDT mation the concentration of NGF in the affected tissue Department of Pharmacology, Yale University School is increased (Constantinou et al. 1994; Donnerer et al. of Medicine, New Haven, CT, USA 1992; Woolf et al. 1994). For example, inflammatory in- [email protected] terleukins that are produced by macrophages and mast cells have been found to trigger the release of NGF from Synonyms keratinocytes in the skin. NGF release is also activated bytumornecrosisfactor(TNFalpha),apotentinflamma- TRPV1, regulation by NGF; Capsaicin receptor, regu- tory peptide. When NGF is injected into rats the animals lation by NGF; VR1, Regulation by NGF; Vanilloid Re- developreducedpawwithdrawalthresholdsformechan- ceptor, Regulation by NGF ical and thermal stimuli (Lewin et al. 1993). After injec- tion of NGF, mechanical and thermal hyperalgesia de- Definition velop with different time courses. Thermal hyperalge-  TRPV1, the receptor for  capsaicin, the pungent sia can be observed within minutes and is thought to be ingredient in chili peppers, is a polymodal receptor for mediated through a peripheral mechanism, whereas me- physical (heat) and chemical painful stimuli in sen- chanical hyperalgesia has a longer onset and is believed sory neurons. The neuropeptide  nerve growth factor to be caused by  central sensitization on the level of the (NGF), which is generated during injury or inflam- spinal cord (Lewin et al. 1993; Lewin et al. 1994). mation, causes  thermal hyperalgesia, an increased The capsaicin receptor, TRPV1, is an ion channel that is sensitivity to thermal stimuli. NGF binds to its receptor, activated by heat and by painful chemical stimuli such TrkA, which activates intracellular signaling pathways as acid (Caterina et al. 1997). Activation of TRPV1 that shift the thermal dependence of TRPV1 activation by capsaicin does not only induce acute pain but it to lower temperatures. also causes thermal hyperalgesia. Heat hyperalgesia TRPV1, Regulation by Protons 2575 is absent in mice deficient in TRPV1 (Caterina et al. 7. Donnerer J, Schuligoi R, Stein C (1992) Increased content and 2000; Davis et al. 2000). In addition, injection of NGF transport of substance P and calcitonin gene-related peptide in sensory nerves innervating inflamed tissue: evidence for a reg- does not result in thermal hyperalgesia in these mice, ulatory function of nerve growth factor in vivo. Neuroscience indicating that TRPV1 might be the downstream target 49:693–698 of NGF signaling in nociceptors. Indeed, when TrkA 8. Kaplan DR, Miller FD (2000) Neurotrophin signal transduction and TRPV1 were co-expressed in a heterologous ex- in the nervous system. Curr Opin Neurobiol 10:381–391 9. Lewin GR, Ritter AM, Mendell LM (1993) Nerve growth factor- pression system, activation of TrkA by NGF resulted in induced hyperalgesia in the neonatal and adult rat. J Neurosci a pronounced sensitization of TRPV1 currents towards 13:2136–2148 temperature, with channels already active below body 10. Lewin GR, Rueff A, Mendell LM (1994) Peripheral and cen- temperature (Chuang et al. 2001). tral mechanisms of NGF-induced hyperalgesia. Eur J Neurosci 6:1903–1912 Recent studies revealed the signaling mechanisms 11. Prescott ED, Julius D (2003) A modular PIP2 binding site that are involved in the sensitization of TRPV1 by as a determinant of capsaicin receptor sensitivity. Science NGF. The initial signaling event after NGF binding is 300:1284–1288 the dimerization of TrkA, followed by autocatalytic 12. Woolf CJ, Safieh-Garabedian B, Ma QP et al. (1994) Nerve growth factor contributes to the generation of inflammatory phosphorylation of tyrosine residues within the intra- sensory hypersensitivity. Neuroscience 62:327–331 cellular domain of the receptor (Kaplan and Miller 13. Zhuang ZY,Xu H, Clapham DE et al. (2004) Phosphatidylinositol 2000). This results in the activation of phospholipase 3-kinase activates ERK in primary sensory neurons and mediates C (PLC) that catalyses the hydrolysis of the mem- inflammatory heat hyperalgesia through TRPV1 sensitization. J Neurosci 24:8300–8309 brane phospholipid phosphoinositol-4,5-bisphosphate (PIP2), yielding inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). PIP2 has been shown to inhibit TRPV1 through interaction with a C-terminal domain TRPV1, Regulation by Protons in the protein (Chuang et al. 2001; Prescott and Julius SVEN-ERIC JORDT 2003). Hydrolysis of PIP2 relieves this inhibition and Department of Pharmacology, Yale University School leads to sensitization of TRPV1 (Chuang et al. 2001). of Medicine, New Haven, CT, USA Biochemical studies revealed that TrkA, TRPV1 and [email protected] PLC proteins interact in vitro and may form a signaling complex. If this interaction occurs in vivo remains to Synonyms be determined (Chuang et al. 2001). In addition to PIP2 hydrolysis by PLC, TrkA activates TRPV1,RegulationbyAcid;Capsaicinreceptor,regula- intracellular kinase pathways that play important roles tion by protons; VR1, Regulation by Protons; Vanilloid in the sensitization of TRPV1 in sensory neurons. One Receptor, Regulation by Protons of the kinases involved is phosphoinositide-3-kinase Definition (PI3K), a kinase that phosphorylates membrane phos- pholipids. PI3K contributes to TRPV1 sensitization  TRPV1, the receptor for  capsaicin, the pungent in- by reducing PIP2 levels in the membrane. In addition, gredient in chili peppers, is a polymodal receptor for PI3K activates downstream kinases such as  ERK physical (heat) and chemical painful stimuli in sen- T that may induce long-term sensitization of the neuron sory neurons. Extracellular acidification, caused by (Bonnington and McNaughton 2003; Zhuang et al. inflammation or tissue injury, increases TRPV1 ac- 2004). tivation through interaction with glutamate residues in the channel protein. References Characteristics 1. Bonnington JK, McNaughton PA (2003) Signalling pathways involved in the sensitisation of mouse nociceptive neurones by Tissue damage produces a variety of chemical medi- nerve growth factor. J Physiol 551:433–446 ators that activate or sensitize nociceptor terminals to 2. Caterina MJ, Schumacher MA, Tominaga M et al. (1997) The elicit pain. An important component of this proalgesic capsaicin receptor: a heat-activated ion channel in the pain path- response is local  acidosis, namely, a reduction in ex- way. Nature 389:816–824 3. Caterina MJ, Leffler A, Malmberg AB et al. (2000) Impaired tracellular pH to levels below the physiological norm of nociception and pain sensation in mice lacking the capsaicin re- ~7.4 (Reeh and Steen 1996). Tissue acidosis has been ceptor. Science 288:306–313 observed in many painful clinical disorders, which 4. Chuang, HH, Prescott ED, Kong H et al. (2001) Bradykinin include inflammation, skeletal muscle and cardiac and nerve growth factor release the capsaicin receptor from   PtdIns(4,5)P2-mediated inhibition. Nature 411:957–962 ischemia, arthritis, hematoma and bone cancer. 5. Constantinou J, Reynolds ML, Woolf CJ et al. (1994) Nerve In chronic cough and asthma, acidification is thought growth factor levels in developing rat skin: upregulation follow- to contribute to the induction of cough through sen- ing skin wounding. Neuroreport 5:2281–2284 sitization of sensory neurons. Tissue acidification is 6. Davis JB, Gray J, Gunthorpe MJ et al. (2000) Vanilloid receptor- 1 is essential for inflammatory thermal hyperalgesia. Nature perceived as painful by humans. Test subjects report a 405:183–187 significant correlation of the perceived intensity of pain 2576 TRPV1, Regulation by Protons

TRPV1, Regulation by Nerve Growth Factor, Figure 1 Sensitization of TRPV1 by nerve growth factor – activated signaling pathways. The capsaicin receptor, TRPV1, is coexpressed with the receptor for nerve growth factor (NGF), TrkA, in the plasma membrane of many sensory neurons. Binding of NGF to TrkA leads to TrkA dimerization and subsequent activation of intracellular signaling. TrkA activates phospholipase C (PLC) and phosphoinositide-3- kinase (PI3K). Both enzymes catalyze reactions that reduce the concentration of the phospholipid phosphoinositol-(4,5)-bisphosphate (PIP2) in the plasma membrane. Whereas PLC hydrolyses PIP2, yielding inositol-triphosphate (IP3) and diacylglycerol (DAG), PI3K phosphorylates PIP2, thereby generating PIP3. PIP2 inhibits TRPV1 currents by direct interaction with the receptor protein. PIP2 removal leads to sensitization of TRPV1, resulting in thermal hyperalgesia.

with decreasing pH when acidic solution is perfused In addition to being sensitive to capsaicin and protons, into the forearm muscle (Issberner et al. 1996). TRPV1 is also activated by noxious heat and is essential Protons cause excitation or sensitization of sensory for  bradykinin-or nerve growth factor-dependent neurons by activating ionic currents across the neu-  thermal hyperalgesia (Caterina and Julius 2001). ral membrane. Two different proton-activated inward TRPV1 is predominantly expressed in small diameter cationic currents have been described (Bevan and Yeats unmyelinated neurons. In these neurons, measure- 1991). One current is sustained and non-desensitizing. ments of capsaicin-activated currents correlate with the The other current is a transient, rapidly activating and presence of the sustained proton-activated current (Be- desensitizing current. In concert with these currents, a van and Geppetti 1994; Petersen and LaMotte 1993). proton-dependent reduction in background potassium The sustained current can be reduced by the TRPV1 conductances has been observed in some neurons that antagonists capsazepine (Liu and Simon 1994) and may contribute to an increase in neural excitability. iodo-resiniferatoxin, indicating that capsaicin and pro- Protons are capable of modulating the activity of a tons use the same target to activate neural excitation. number of cloned receptors and ion channels expressed The effectiveness of TRPV1 antagonists, especially by primary afferent nociceptors. Pharmacological,  capsazepine, is strongly dependent on the species electrophysiological and genetic evidence suggest used in the individual studies. Whereas proton-induced that the capsaicin receptor, TRPV1, is underlying the fiber responses in guinea pigs are strongly reduced by sustained proton-activated current, whereas different capsazepine, responses in rodents are less affected. combinations of  ASICs (acid sensitive ion channels However, new high-affinity TRPV1 antagonists such as of the degenerin family) may give rise to transient BCTC (N-(4-tertiarybutylphenyl)-4-(3-chloropyridin- acid-sensitive currents (Krishtal 2003). In addition, 2-yl)-tetrahydropyrazine-1(2H)-carboxamide) are very ATP-gated channels (P2X-receptors) and background effective at blocking proton-induced fiber responses in potassium channels (TASK-channels) have been shown rats at nanomolar concentrations. Capsaicin-activated to be modulated by protons. currents in sensory neurons show sensitivity to ex- The capsaicin receptor, TRPV1, is a nociceptor-specific tracellular acidification. For example, a decrease in cation channel that serves as the molecular target for extracellular pH from 7.3 to 6.3 leads to a seven-fold capsaicin, the main pungent ingredient in “hot” chili potentiation of the capsaicin-activated current (300 nM) peppers (Caterina et al. 1997). TRPV1 is a member of in dissociated rat sensory neurons (Petersen and LaM- the transient receptor potential (TRP) ion channel gene otte 1993). Single ion channel recordings from sensory family that includes several other channels involved in neurons show that acidification leads to a dramatic sensory transduction, such as  TRPM8, the receptor increase in the open probability of capsaicin-activated for cold temperature and  menthol,and TRPV2,a channels, whereas the single channel conductance is channelactivatedathightemperatures(Jordtetal.2003). slightly diminished (Baumann and Martenson 2000). TRPV1, Regulation by Protons 2577

TRPV1, Regulation by Protons, Figure 1 Activation and modulation or TRPV1 by protons (left): TRPV1 currents recorded from a TRPV1−expressing Xenopus oocyte are shown, recorded at a membrane voltage of -40 mV. TRPV1 channels were first activated for 20 s by acidic solution (pH 4.0) at room temperature, inducing a rapidly activating inward current. To record heat-activated currents, the bath temperature was then elevated from room temperature to 47˚C within 10 s (red bar). This procedure was repeated seven times in 2 min. intervals. During the fifth heat application, the bath pH was decreased from 7.6 to 6.3. Heat activated currents are potentiated >2-fold by the drop in pH.Localization of proton-sensing residues in the TRPV1 channel (right): TRPV1 has a transmembrane moiety with six putative transmembrane domains and a P-loop structure between transmembrane domains 5 and 6 that contributes to the ion permeation pathway. The N- and C-termini are localized intracellularly. Two glutamate residues (E) are essential for regulation by protons (E600) and activation by protons (E648). Both residues are in or near the putative pore domain of the channel protein.

The analysis of mice with a targeted deletion in the gene of other sensitizing factors (e.g. bradykinin or  nerve encoding for TRPV1 provided further evidence for an growth factor), even moderate acidification can lead to important role of TRPV1 in proton-dependent signaling strong activation of TRPV1. in sensory neurons. In these mice, proton-activated sus- The capsaicin receptor is a non-selective cation chan- tained currents in DRG neurons were absent and proton- nel with a central ion pore. The channel is formed activated Ca2+-uptake was greatly diminished (Caterina by four homomeric protein subunits. Each monomer et al. 2000). In addition, recordings in the skin-nerve- has a transmembrane moiety with six predicted trans- preparation showed a dramatic reduction in the preva- membrane domains and extended cytosolic N-terminal lence of proton-sensitive C-fibers. and C-terminal domains. The transmembrane moiety In heterologous systems, TRPV1 channels are acti- contains a region, the P-loop between the fifth and vated by extracellular protons in the absence of other sixth transmembrane domains, that contributes to the T activating stimuli, such as capsaicin or heat. When ex- ion conduction pathway of the central pore. Extensive pressed in cultured mammalian cells, protons activate site-directed mutagenesis studies pinpointed putative TRPV1 starting at pH around 6.5, with a half maximal proton interaction sites to regions near or within the activation at pH 5.4 (Tominaga et al. 1998). These pore domain of the channel (Jordt et al. 2000; Welch et currents are inhibited by TRPV1 antagonists. Like the al. 2000). In particular, two glutamate residues, at posi- situation in the native neuron, the degree of inhibition tions E600 and E648 in the rat protein, were identified depends on the individual antagonist and differs be- as essential for the regulation and activation of TRPV1 tween TRPV1 species homologs. For example, proton by protons. Negatively charged glutamate residues can activated human and guinea pig TRPV1 channels are serve as acceptors for protons. In addition, glutamate more strongly inhibited by capsazepine than rat TRPV1 residues may interact with permeating cations near or channels. in the conduction pathway. These mutagenesis studies The potentiation of capsaicin-activated currents by pro- also provided further evidence that protons play a dual tons in sensory neurons can be recapitulated with cloned role in the activation of TRPV1. Mutations introduced TRPV1 channels. More importantly, it was found that at position E600 dramatically shifted or eliminated the protons also potentiate heat-activated TRPV1 currents, pH-dependenceofheat-andcapsaicin-activatedTRPV1 effectively lowering the temperature activation thresh- currents. On the other hand, mutations at position E648 old of TRPV1 channels during persistent activation and led to a significant reduction in proton-activated cur- increasing current amplitudes (Tominaga et al. 1998). rents, whereas heat- and capsaicin-activated currents This indicates that at body temperature, and especially maintained their pH-dependence. These results indi- in inflammatory situations with elevated concentrations cated that the modulation of TRPV1 currents by protons 2578 TSK and direct channel gating by protons can be separated the nerves and by the presence of one to a few sharply at the structural level. defined, anesthetic, hypopigmented skin lesions.  Hansen’s Disease References 1. Baumann TK, Martenson ME (2000) Extracellular protons both increase the activity and reduce the conductance of capsaicin- gated channels. J Neurosci 20:RC80 Tubo-Ovarian Complex 2. Bevan S, Geppetti P (1994) Protons: small stimulants of capsaicin-sensitive sensory nerves. Trends Neurosci 17:509–512  3. Bevan S, Yeats J (1991) Protons activate a cation conductance in Chronic Pelvic Pain, Pelvic Inflammatory Disease a sub-population of rat dorsal root ganglion neurones. J Physiol and Adhesions (Lond) 433:145–161 4. Caterina MJ, Julius D (2001) The vanilloid receptor: a molecular gateway to the pain pathway. Annu Rev Neurosci 24:487–517 5. Caterina MJ, Schumacher MA, Tominaga M et al. (1997) The Tumor (National Cancer Institute capsaicin receptor: a heat-activated ion channel in the pain path- Terminology – Neoplasm) way. Nature 389:816–824 6. Caterina MJ, Leffler A, Malmberg AB et al. (2000) Impaired nociception and pain sensation in mice lacking the capsaicin re- Definition ceptor. Science 288:306–313 7. Issberner U, Reeh PW, Steen KH (1996) Pain due to tissue acido- Anabnormalmassoftissuethatresultswhencellsdivide sis: a mechanism for inflammatory and ischemic myalgia? Neu- more than they should or do not die when they should. rosci Lett 208:191–194 Tumors may be benign (not cancerous), or malignant 8. Jordt SE, Tominaga M, Julius D (2000) Acid potentiation of the (cancerous). capsaicin receptor determined by a key extracellular site. Proc  Natl Acad Sci USA 97:8134–8139 Cancer Pain Management, Treatment of Neuropathic 9. Jordt SE, McKemy DD, Julius D (2003) Lessons from peppers Components and peppermint: the molecular logic of thermosensation. Curr Opin Neurobiol 13:487–492 10. Krishtal O (2003) The ASICs: signaling molecules? Modulators? Trends Neurosci 26:477–483 Tumor Necrosis Factor Alpha(α) 11. Liu L, Simon SA (1994) A rapid capsaicin-activated current in rat trigeminal ganglion neurons. Proc Natl Acad Sci USA 91:738–741 Synonyms 12. Petersen M, LaMotte RH (1993) Effect of protons on the inward α current evoked by capsaicin in isolated dorsal root ganglion cells. TNF Alpha( ) Pain 54:37–42 13. Reeh PW, Steen KH (1996) Tissue acidosis in nociception and Definition pain. Prog Brain Res 113:143–151 TNFα is a pro-inflammatory cytokine and member of 14. Tominaga M, Caterina MJ, Malmberg AB et al. (1998) The cloned capsaicin receptor integrates multiple pain-producing stimuli. the ’TNF-superfamily’, with algesic actions. It partici- Neuron 21:531–543 pates in inflammation, wound healing and remodeling 15. Welch JM, Simon SA, Reinhart PH (2000) The activation mech- of tissue. anism of rat vanilloid receptor 1 by capsaicin involves the pore  Cytokines as Targets in the Treatment of Neuropathic domain and differs from the activation by either acid or heat. Proc Natl Acad Sci USA 97:13889–13894 Pain  Inflammatory Neuritis  Wallerian Degeneration TSK Twin Studies  Tampa Scale for Kinesiophobia Definition The comparison of traits among pairs of monozygotic TTX (MZ; identical) versus dizygotic (DZ; fraternal) twins. MZ twins are clones, sharing 100% of their DNA se-  Tetrodotoxin quence,whereasDZtwinsshareonly50%(nomorethan any other siblings). If a painful pathology occurs more often in both individuals in a MZ twin pair than a DZ Tuberculoid Leprosy twin pair, it can be said to be heritable. A caveat is that this analysis is dependent on the assumption of equal environments of MZ and DZ twins, which may not be Definition realistic. The relatively benign and least infectious type of lep-  Heritability of Inflammatory Nociception rosy, which is characterized by early severe damage to  Heritable Tyrosine Kinase A 2579

Twitch-Obtaining Intramuscular Type-2 Reaction (Leprosy) Stimulation Synonyms Definition Erythema Nodosum Leprosum This is a technique of dry needling developed by Chu, using an EMG needle to perform dry needling. Definition  Dry Needling A leprosy reaction resembling an Arthus reaction and representing humoral hypersensitivity. It is due to an antigen-antibodyreactionwiththeformationofimmune Two Pore Domain K+ Channels complexes at the site of antigen deposits in various tis- sues and gives rise to acute inflammatory foci. It is Definition characterized by painful red nodules or plaques, and distributes especially on the face and limbs. It may be A large, structurally related, class of K+ channels that associated with severe systemic and visceral symptoms. provide a large fraction of the background conductance  Hansen’s Disease in many neurons. They are modulated by a variety of physical (temperature, mechanical) and chemical stim- uli (pH, anesthetics, lipids).  Nociceptors, Cold Thermotransduction Type-II Receptors

Definition Two-Way Scaling Models Type II receptors are G-protein coupled receptors with 7 transmembrane domains. Definition  Opioid Modulation of Nociceptive Afferents In Vivo Two-way scaling models yield only the group stimulus space; individual differences are lost.  Multidimensional Scaling and Cluster Analysis Ap- plication for Assessment of Pain Tyrosine Kinase A

Synonyms Type-1 Reaction (Leprosy) trkA Synonyms Definition T Reversal reaction The biological actions of neurotrophins are mediated by specific neurotrophin receptor tyrosine kinases (trks). Definition The proto-oncogene trkA is now recognized as the A leprosy reaction usually occurring during chemother- primary high affinity receptor for nerve growth fac- apy in borderline leprosy, representing a delayed hyper- tor (NGF), while two related tyrosine kinase receptors, sensitivity reaction with upgrading of cell-mediated im- trkB and trkC, mediate the biological functions of brain- munity to Mycobacterium leprae. It is characterized by derivedneurotrophicfactor(BDNF)andneurotrophin-3 erythema, edema, and tenderness of preexisting skin le- (NT-3), respectively. sions, neuritis with nerve damage, and fever.  ERK Regulation in Sensory Neurons during Inflam-  Hansen’s Disease mation