Computational Functions of Neurons and Circuits Signaling Injury: Relationship to Pain Behavior

Computational functions of neurons and circuits signaling injury: Relationship to pain behavior

Lorne M. Mendell1

Department of Neurobiology and Behavior, State University of New York, Stony Brook, NY 11794

Edited by Donald W. Pfaff, The Rockefeller University, New York, NY, and approved November 3, 2010 (received for review August 16, 2010) The basic circuitry of the “pain pathway” mediating transmission cording from a population of small-diameter axons with proper- of information from the periphery to the brain is well known, ties of nociceptors. It is now well established that nociceptors consisting of specialized sensory fibers known as nociceptors pro- are a distinct population of sensory fibers with unique physio- jecting to specific spinal cord neurons, which in turn project on to logical, anatomical, and chemical properties. However, as we the thalamus and cerebral cortex. Here we survey some of the shall see below, activation of nociceptors can be prevented from unique properties of these circuits, such as peripheral and central causing pain, and conversely, pain is reported in situations in sensitization, and the segmental and descending modulatory con- which nociceptors are not activated. trol of synaptic transmission. We also review evidence indicating The defining characteristic of nociceptors is their high thresh- dissociation between nociceptor activity and behavioral indica- old to natural stimulation of their receptive field. This has been tions of pain. Together, these considerations point to the need investigated mostly in skin, but nociceptors exist also in muscle for a more quantitative approach to the nociceptive system, spe- and viscera. The initial work from Perl’s laboratory in the cat cifically the interactions at peripheral, spinal, and supraspinal lev- demonstrated that nociceptors could be subdivided into two els as well as between them, to more fully understand how the general groups: high-threshold mechanoreceptors whose axons activity in nociceptive neurons individually and collectively is re- conduct in the small myelinated Aδ range, and polymodal noci- lated to the pain response. ceptors sensitive to a range of modalities, including mechanical, thermal, and/or chemical, with unmyelinated C-fiber axons (6). neurotrophin | nociceptive system plasticity | gain control | gate theory | Studies using these defining characteristics as starting points have rostral ventromedial medulla revealed many additional unique characteristics of nociceptors, including their Na channel composition (9–11), their action po- his brief review surveys our current understanding of how tential configuration (12, 13), their receptors for numerous in- Tactivity in pathways activated by nociceptors contributes to the flammatory molecules (14), their transmitters (15, 16), and their experience of pain. In attempting this task we must recognize projections into the spinal cord (17, 18). certain difficulties at the outset, particularly the fact that the same stimulus might or might not be considered painful, depending on Relationship of Peripheral Nociceptors to Pain factors such as sex (1) and the genetic profile of the individual (2). The recent advances in genetic methods have offered the op- More significantly, the pain produced by a nociceptive stimulus in portunity to test the effects of removing individual molecular the same individual is influenced by situational variables, for ex- receptor classes or specific classes of nociceptors on the ability ample the level of stress, as part of the adaptive response to such to respond to nociceptive stimuli. Because of evidence that the challenges (3). To help explain this property of nociception, we TRPV1 receptor responds to noxious heat with a threshold will focus on the modifiability of these neurons and circuits be- (43 °C) that is very close to the threshold for heat pain (19), it cause this is an important determinant of the failure of activated was expected that knockout mice lacking the TRPV1 receptor nociceptive afferents to elicit a stereotyped pain response. would be unresponsive to noxious thermal stimulation. Dissoci- ated dorsal root ganglion cells from these preparations exhibited Periphery the expected loss of sensitivity to noxious heat, but the mice The concept of a neural mechanism for pain was advanced ex- themselves displayed largely normal responses to noxious heat plicitly by the 17th century philosopher René Descartes, who (20, 21). However, they exhibited a deficit in sensitization to posited a neural “channel” connecting the site of peripheral noxious agents such as carrageenan. The full explanation for these damage to the brain. The concept of the nociceptor was in- findings is not yet available. One possibility is that receptor(s) troduced more than 100 y ago by Sherrington (4), who defined it other than TRPV1 respond to thermal stimulation but are not as a sensory receptor responsive to stimuli that are potentially subject to sensitization. DRG cells expressing the unknown re- damaging to the organism; more precisely that in the skin there ceptor might be either very fragile or rare and thus unlikely to be had evolved “a special sense of its own injuries.” His focus on observed in dissociated cell culture. reflex action led him further to postulate that the action of A more recent approach has involved eliminating entire nociceptors would lead to withdrawal of the affected body part populations of nociceptors and evaluating the resulting behav- from the source of damage (5). Electrical stimulation of periph- ioral sensory loss. Cavanaugh et al. (22) have used genetic and eral nerves revealed a characteristically high threshold for the pharmacological approaches to selectively eliminate entire clas- fl fl withdrawal re ex compared with proprioceptive re exes; this was ses of nociceptors. In mice peptidergic nociceptors cells termi- interpreted as indicating that the peripheral axons responsible were relatively inexcitable (i.e., were small myelinated or un-

myelinated rather than large myelinated) (6). Early attempts to This paper results from the Arthur M. Sackler Colloquium of the National Academy of record the adequate stimulus for such fibers were only partially Sciences, “Quantification of Behavior” held June 11–13, 2010, at the AAAS Building in successful, in large part because of the difficulty in recording from Washington, DC. The complete program and audio files of most presentations are available individual small fibers. This left open the possibility that pain on the NAS Web site at www.nasonline.org/quantification. results from patterned activity in sensory fibers also sensitive to Author contributions: L.M.M. analyzed previously published data and wrote the review. nonnoxious stimuli rather than activity in a special population of The author declares no conflict of interest. nociceptors. This uncertainty was resolved in the late 1960s and This article is a PNAS Direct Submission. early 1970s when Perl and collaborators (7, 8) succeeded in re- 1E-mail: [email protected].

www.pnas.org/cgi/doi/10.1073/pnas.1012195108 PNAS Early Edition | 1of6 Downloaded by guest on October 2, 2021 nating in lamina I were selectively killed by treatment with receptors (27). This might provide an additional basis for vari- capsaicin. In companion experiments using transgenic mice, a able filtering based on the spike intervals associated with the different population of polymodal nociceptors terminating in responses of the different afferent fiber classes to specific sti- outer lamina II (lamina IIo) and expressing a unique G protein- mulus modalities. coupled receptor (MGPCR) could be selectively killed after These data suggest that certain pathways projecting from cells treatment with diphtheria toxin. Because both of these pop- in different laminae of the dorsal horn are specialized to abstract ulations are polymodal nociceptors, it was expected that elimi- certain aspects of the information coded in the discharge of nation of either class would result in a similar behavioral deficit polymodal nociceptors. This may be important in helping the involving noxious heat and high-threshold mechanical stimula- organism distinguish between the different modalities to which tion. An unexpected result was obtained, namely that eliminating the polymodal nociceptors can respond. The details of this virtually all peptidergic nociceptors terminating in lamina I re- computational achievement remain to be fully understood. duced sensitivity to thermal nociception but not to mechanical nociception. The opposite result was obtained when the Sensitization MGPCR-expressing polymodal nociceptors projecting to lamina One of the hallmarks of nociceptive pathways is sensitization in IIo were eliminated (i.e., mechanical nociceptive threshold was response to a damaging stimulus whereby the behavioral re- elevated but thermal nociception threshold was unaffected). sponse to subsequent stimuli is enhanced. In some cases nor- fi fi It is dif cult at present to give a de nitive interpretation of mally nonnociceptive stimuli elicit pain because of a decrease in these unexpected results. They suggest that the information threshold (allodynia); in others, a normally painful stimulus coded in the discharge of the nociceptors does not affect be- becomes even more painful (hyperalgesia). Two general mech- havior directly; only certain components seem to affect behavior: anisms have been identified (Fig. 1): one acting at the periphery noxious heat in the case of the TRPV1-expressing nociceptors (peripheral sensitization) and the other acting centrally (central projecting to lamina I and mechanical nociception in the case of sensitization). Peripheral sensitization results from injury-induced the MGPCR-expressing nociceptors projecting to lamina IIo. One possible interpretation is that subtle variations in the dis- release of a number of sensitizing agents from damaged cells charges associated with the different modalities are filtered dif- and also from immune-competent cells recruited into the vicinity ferently by synapses in the pathways projecting to lamina I and of the nociceptive nerve terminals (28). These substances act to either reduce the threshold or enhance the magnitude of the lamina IIo owing to differences in discharge properties, synaptic properties, or both. Synaptic filtering is known to vary at synap- response to a given stimulus. These sensitizing agents have ses, for example those made between group Ia stretch-sensitive been referred to collectively as the “inflammatory soup.” Central spindle afferents and different target motoneurons (23, 24). An sensitization of nociceptive pathways has been studied in most additional factor that might contribute to filtering the trans- detail in the spinal cord (29), although there is evidence that mitted nociceptive discharge is the contribution of NMDA similar mechanisms occur at synapses in other regions of the receptors in the postsynaptic cells (25, 26), which cause sub- nociceptive system (30). As with peripheral sensitization, a num- stantial nonlinearity in the transmission process due to the ber of molecules and signaling pathways are involved in eliciting voltage dependence of the Mg2+ block associated with these central sensitization (29).

Fig. 1. Schematic diagram of major mechanisms involved in peripheral and central sensitization. Injury results in release of inflammatory mediators (inflammatory soup) that enhance the nociceptor discharge produced directly by the injury. The increased activity in sensory neurons results within hoursin increased levels of peptide (calcitonin gene-related peptide, substance P, BDNF) in the dorsal root ganglion and subsequent release of these into the spinal cord and into the injured tissue. Two frequency-dependent effects occur in the spinal cord: short-term temporal summation, known as windup (supported by peptide release), and LTP. Both of these require NMDA receptor activity in superficial dorsal horn neurons. Many other receptors in dorsal horn neurons − contribute to the enhanced activity (e.g., trkB and NK1). Activated microglia also release BDNF, which can decrease ECl via effects on the KCC2 transporter, thereby converting inhibitory actions into excitatory ones, thus resulting in increased discharge in nociceptive pathways. Influx of Ca2+ participates in second messenger activation of gene transcription mechanisms, which prolongs the effect of nociceptor activity.

2of6 | www.pnas.org/cgi/doi/10.1073/pnas.1012195108 Mendell Downloaded by guest on October 2, 2021 A fundamental question for both peripheral and central sen- release from spinal terminals of nociceptive afferents and sitization is how the different molecular mechanisms interact. In inhibits the KCC2 chloride transporter in relay cells, thereby the case of peripheral sensitization a number of molecules, in- converting GABA-driven hyperpolarization to depolarization cluding bradykinin, prostaglandin, histamine, and NGF, are re- (39). The interaction of these effects of BDNF in the spinal cord leased, generally in response to an inflammatory injury. They remains to be evaluated. Although trkB agonists have been im- are released from immune-competent cells, such as mast cells, plicated mainly in central sensitization, BDNF and NT-4/5 also macrophages, and neutrophils, recruited into the injured region. sensitize the discharge of nociceptors (40–42). Each agent acts on the nociceptive nerve ending via its receptor: BK-receptors for bradykinin, EP-receptors for prostaglandin, Nociceptive Circuits in the Spinal Cord and Brain H-receptors for histamine, and trkA receptors for NGF, etc. It is Cells in the dorsal horn responding to nociceptive inputs are of not clear whether these molecules play a similar role and are two general types: nociceptive specific (NS) and wide dynamic redundant to ensure pain and subsequent guarding of inflamed range (WDR). NS neurons are located primarily in lamina I and tissues, or whether they have independent roles to play in elic- the outer portion of lamina II (lamina IIo). These cells receive iting inflammatory pain. The potential for interaction among their primary afferent input exclusively from nociceptors, either these agents exists at the level of intracellular signaling in the Aδ-fibers (lamina I) or C-fibers (lamina IIo), and respond ex- nociceptive nerve terminal (e.g., PKA and/or PKC), but it is also clusively to nociceptive inputs. In deeper laminae of the dorsal possible that interaction takes place at the level of the inflam- horn are cells that receive input from Aβ- and Aδ-peripheral fl matory cells whose output can in uence the release from other fibers as well as input from nociceptive cells in the superficial fl fl in ammatory cells (e.g., release from mast cells is in uenced by laminae. This convergent input makes them responsive to both NGF). There is some evidence in behavioral experiments for gentle and noxious stimulation, hence the descriptor WDR. interaction between the effects of these different agents (31), but Both WDR and NS cells project from the spinal cord to the few studies of this sort are available. Another way of framing this brain. The major ascending pathway is via the crossed spino- in problem is to ask whether these sensitizing mechanisms act thalamic tract. Many such cells terminate in the somatosensory series in parallel or . It seems likely that both types of interaction nuclei in the lateral thalamus, particularly the ventrobasal nu- operate to determine the level of peripheral sensitization. Because cleus; the midline intralaminar nuclei of the thalamus are an- many pharmacological interventions in pain involve interfer- other major termination site of spinothalamic axons (43). Cells in ence with single mechanisms (e.g., aspirin inhibiting prostaglan- the ventrobasal nucleus project largely to the SI somatosensory din synthesis), it is important to resolve the mechanisms linking cortex, whereas the midline intralaminar nuclei project to the injury and discharge properties of nociceptors at a computa- anterior cingulate cortex (ACC). Other destinations of thalamic tional level. cells are the insular cortex and SII. There is considerable species As pointed out above, nociceptors are unique in releasing variation in the pattern of thalamo-cortical projections. We will peptidergic transmitters such as substance P and calcitonin gene- see below that these different cortical regions are concerned with related peptide into the spinal cord in addition to the common different components of the nociceptive stimulus and its trans- excitatory transmitter glutamate. This prolongs the depolarization formation into the pain response. of postsynaptic cells, resulting in temporal summation in response Some ascending fibers carrying nociceptive information from to successive stimuli, originally described as windup (32). The the spinal cord terminate caudal to the thalamus in the nucleus result is a discharge of increasing length in response to successive of the rostral ventromedial medulla (RVM), and in the peri- C-fiber volleys, provided they are elicited no more than a few seconds apart. Responses to A-fiber stimulation do not exhibit this aqueductal gray (PAG) in the midbrain. These projections acti- temporal summation. In accordance with this pattern, it has been vate systems that feed back to the spinal cord to modulate the found that “first pain” elicited by activity in Aδ-fibers does not input from nociceptors (see below). “ ” sensitize with successive stimulation, whereas second pain eli- Processing the Nociceptive Message cited by activity in C-fibers does sensitize, with parameters con- sistent with a role for windup (33). We have already discussed evidence that processing the noci- The cumulative depolarization of second-order cells has con- ceptive message may not be straightforward because deleting a population of nociceptors does not necessarily predict the sequences beyond the increased impulse activity because the fi postsynaptic cells in the superficial dorsal horn activated by no- behavioral de cit. A parallel conclusion can be drawn from ciceptive inputs have NMDA receptors in addition to AMPA studies of central pathways responding to activation of the receptors. The NMDA receptors become permeable to Ca2+ nociceptors. For example, behavioral experiments in the tri- when subjected to depolarization, and this acts as a second geminal system with recordings from NS and WDR neurons have messenger initiating a series of events that can lead to long- revealed that the magnitude of nociceptive stimuli is coded by lasting transcriptional changes in gene activity (29). NMDA WDR cells, not by NS cells (44). The role of NS cells is not well receptors also contribute to another use-dependent long-term established, although there have been suggestions that lamina I potentiation (LTP) of activity in postsynaptic cells in the super- NS neurons project via a “private” pathway to the thalamus and ficial dorsal horn. Unlike the windup, which does not require that from there this information is relayed to the anterior cin- high-frequency activity, LTP lasts for hours. Application of this gulate and insular cortex (45). The role of this system according stimulus paradigm to the human forearm also results in long- to its proponents is a homeostatic one, similar to temperature lasting behavioral sensitization (34). processing, whereby the body maintains an equilibrium state in As with peripheral sensitization, there are numerous mecha- response to the nociceptive stimulus. nisms contributing to central sensitization. The neurotrophin Neurons in the somatosensory cortex seem highly specialized BDNF plays an important role. BDNF is up-regulated in the for discriminative aspects of pain because they have small re- soma of nociceptors several hours after the onset of peripheral ceptive fields, unlike cells in the ACC, which have whole-body sensitization (35, 36), produced for example by NGF. This receptive fields (46). The function of ACC has been best eluci- BDNF is released into the superficial dorsal horn (37), and it has dated using PET imaging to measure activity in conscious human been shown to sensitize the synaptic response of AMPA recep- experimental subjects. The findings from these experiments tors in cells of lamina II via a PKC-dependent mechanism (38). suggest that anterior cingulate cortical activity is related to the BDNF plays another role in central sensitization: it is released unpleasantness of a painful stimulus rather than its magnitude from microglia in the superficial dorsal horn activated by ATP (47). ACC projections to the amygdala indicate a close connec-

Mendell PNAS Early Edition | 3of6 Downloaded by guest on October 2, 2021 tion with the “emotional brain,” which adds an important af- fective component to the response to the painful stimulus. Circuits That Control Nociceptive Input to the Brain Numerous studies in the past 50 y have revealed that nociceptive pathways are subject to control at many different levels. The gate theory of pain proposed by Melzack and Wall (48) was a land- mark in this area because it suggested that activation of large- diameter afferents exerted a mixed excitatory and inhibitory effect on spinal neurons transmitting nociceptive information to the brain, whereas small-diameter afferents elicited a purely excitatory influence on the activity of these cells. They suggested that it was the balance in activity between small- and large- diameter sensory fibers that determined the level of nociceptive activity forwarded to the brain. Although some details of the circuitry proposed in that article (48) were not confirmed, particularly the idea that small-diameter afferents resulted in presynaptic disinhibition of cutaneous inputs to the spinal neurons (49, 50), the ideas expressed by these authors opened a signifi- cant new chapter in studies of nociceptive pathways. One important outcome was the suggestion that pain might be modified by selective electrical stimulation of large-diameter fibers in peripheral nerve (transcutaneous electrical nerve stimulation) (51) or via dorsal column stimulation (52). This has proven to be very useful clinically in certain painful conditions (53), although the mechanism is probably more complex than the original proposal based on the gate theory because the pain relief can persist for up Fig. 2. Simplified diagram displaying some of the potential major inter- to hours after the large fiber stimulation is stopped, possibly actions between different levels of the nociceptive system; the sign of the because of the involvement of opiate mechanisms (54, 55). effect is given only in the dorsal horn of the spinal cord and the RVM. fl Segmental inputs to the superficial dorsal horn from Aδ- and C-fibers are Another system with strong in uence on transmission from β fi afferent activity in nociceptors to spinal transmission neurons excitatory (+). Inputs from A - bers also have an inhibitory component (denoted +/−) as described in the gate theory (see text). The specific path- originates from the RVM (Fig. 2) (3). Two major groups of fi fi fi ways mediating the inhibition are not speci ed in this gure. Descending neurons projecting to the spinal cord have been identi ed from ON and OFF cells from the RVM can excite and inhibit transmission, re- recordings in vivo. OFF cells are tonically active and have an spectively, from peripheral nociceptive afferent fibers to cells in the spinal inhibitory action on nociceptive transmission in the spinal cord. dorsal horn. OFF cells are excited and ON cells are inhibited by projections ON cells are normally silent and facilitate nociceptive trans- from PAG. In turn, the PAG is influenced by projections from hypothalamus mission (56). Ascending activity elicited by a painful stimulus and amygdala and indirectly through these nuclei from the ACC. RVM, RVM, inhibits OFF cells and increases activity in ON cells, which act PAG, and hypothalamus are also influenced by ascending connections from the spinal cord, providing the substrate for multiple feedback loops influ- together to amplify the spinal effects of the nociceptive activity, fi for example in facilitating the withdrawal response (57). Opiates encing transmission from primary afferent bers to spinal neurons. influence activity in OFF and ON cells oppositely, with OFF cells being facilitated and ON cells being inhibited. This combination sponse to stimulation that does not include nociceptors). For acts to reduce the gain of nociceptive pathways at the level of the example, human subjects report pain from placing their hand on dorsal horn when opiate receptors are activated. The RVM is a series of bars arranged such that cool and warm bars alternate influenced by higher centers such as the PAG in the midbrain, (#1, #3, etc. cool; #2, #4, etc. warm; referred to as a thermal which in turn receives input from cortical centers including the grill); touching the individual bars of either temperature is not ACC and thus plays a role in conditioning nociceptor input as painful. The report of pain in the absence of nociceptors acti- a function of behavioral context. This system has also been vation is called the thermal grill illusion (61). Imaging the brain proposed to play a role in the analgesia reported in response to placebo administration; the reduced pain is associated with ac- of subjects touching the thermal grill reveals paradoxical acti- tivation of descending pathways emanating from cingulate cortex vation of areas associated with pain (i.e., the insula and ACC), (58) and is mediated by opiate receptor activity (59). but these areas are not activated by the cool and warm tem- Administration of peripheral sensitizing agents affects the peratures touched individually (62). The authors have advanced balance of activity in the ON and OFF cells in the RVM (57). a computational model based on recordings from lamina I cells This suggests that this system can set the gain of the spinal no- in the spinal cord; they found that cells responding exclusively to fi ciceptive pathway on a moment-to-moment basis. the cool temperature had a signi cantly decreased response to A more diffuse inhibitory mechanism has been demonstrated the grill stimulus (using the same cool temperature), whereas in experimental animals and human subjects. Known as diffuse a different population of lamina I cells responsive to noxious noxious inhibitory control (DNIC), this mechanism acts over the heat, pinch, and cool (HPC cells) displayed no change in re- entire body, such that inputs from one region (e.g., the head) can sponse when tested with the grill. They postulate that cells re- inhibit inputs from any other part of the body (e.g., the hind sponsive to cool stimuli inhibit the responsiveness of thalamic or limb/leg) (60). This mechanism is independent of the PAG/RVM cortical cells to inputs from HPC cells. Thus, the cool stimuli in system described above and has been suggested to suppress weak the thermal grill cause disinhibition of neurons coding the nociceptive inputs in favor of the strongest ones. “painfulness” of the stimulus (HPC cell discharge). The inhibitory mechanisms outlined above provide a potential explanation for the finding that activation of nociceptors does Perspective not necessarily result in the experience of pain. There are also It is clear from this brief summary that input from nociceptors examples of the reverse (i.e., when pain is experienced in re- can be affected by changes in excitability of the sensory neurons

4of6 | www.pnas.org/cgi/doi/10.1073/pnas.1012195108 Mendell Downloaded by guest on October 2, 2021 themselves as well as their synapses in the spinal cord. The periphery, changes in synaptic efficacy in the spinal cord, and nociceptor discharge is influenced at the periphery by sensitiza- alterations in the balance of excitatory and inhibitory inputs. In tion mechanisms driven by substances released in the vicinity of the case of neuropathic pain caused by damage to peripheral the sensory terminals during a diverse group of events associated nerves or central pathways, structural plasticity (e.g., collateral with inflammation. Beyond that, the transmission of the noci- sprouting) might be expected to occur because of partial de- ceptive message is subject to modulation by segmental, nervation of neurons resulting from the injury. descending, and ascending inhibitory mechanisms. The latter The multiplicity of changes makes evaluation of any specific seem to consist of at least two different types of pathways, some strategy very difficult, particularly in view of the potential for local and another (DNIC) more global. interaction among these different mechanisms. For example, Not surprisingly, much of the interest in these mechanisms has there is evidence that descending control mechanisms from the been driven by attempts to attenuate persistent or chronic pain RVM are altered in a time-dependent manner after inflam- in disease states. In the case of peripheral sensitization these matory injury (57). Thus, any treatment of the pain at the pe- efforts are driven toward conditions such as arthritis, burns, or riphery might have paradoxical effects due to changes in function headache and involve the use of inhibitors of cyclooxygenase of the descending control mechanism. These considerations call enzymes responsible for prostaglandin synthesis (63). Other for a more integrated and quantitative approach to the behavior agents, such as molecules with anti-NGF activity, are currently of the nociceptive pathway. A problem that requires attention in being tested for a possible therapeutic role in certain types of this regard is how any manipulations should be evaluated. The pain (64). Segmental control mechanisms have been activated most realistic measure is behavior, because this is the desired using electrical stimulation of peripheral nerves or their rostral endpoint and because it is carried out in the absence of anes- projection in the spinal cord (53). Descending systems have been thesia, which interferes with evaluation of pain mechanisms. manipulated in most cases by delivery of opiates because the However, this is complicated in nonhuman species such as cingulate cortex→PAG→RVM→spinal cord descending control rodents owing to the inability to obtain direct measures (reports) system expresses opiate receptors at every site, and on balance, of pain intensity. Brain activity might be a useful surrogate, but activation of this system acts to inhibit nociceptive input to the because multiple brain regions acting together are probably re- spinal cord (65). This list is not exhaustive; other pharmacolog- sponsible for the pain behavior, this would be difficult to in- ical approaches to pain at the spinal level include the tricyclic terpret unless the combinatorial rules were understood. Thus, antidepressants, NMDA receptor blockade, and Ca channel blockers (66). Although there has been modest success in con- despite tremendous progress in establishing neuronal pathways, trolling pain pharmacologically, there remain serious deficits. cellular and physiological mechanisms, and molecular entities Significantly, neuropathic pain caused by direct injury to the involved in conversion of nociceptors activity to pain behavior, peripheral nerves or the spinal cord is relatively refractory to it is clear that we require more information on the behavior of control by these methods (67). Furthermore, these drugs all have this system as a whole as well as the interactions between the side effects, some quite serious, such as addiction, gastrointes- different components to enhance our ability to better treat tinal bleeding, etc. painful conditions. One of the hallmarks of chronic pain is its association with fl ACKNOWLEDGMENTS. I thank Dr. Vanessa Boyce for useful comments on plasticity of the nociceptive system. In the case of in ammatory a draft of the manuscript. My research was supported by National Institutes pain this plasticity is largely functional, involving increases in of Health Grant 5RO1 NS-16996, the Christopher and Dana Reeve Founda- the number and sensitivity of high-threshold receptors at the tion, and the William Heiser Foundation.

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