Afferent Pain Pathways: a Neuroanatomical Review

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Brain Research 1000 (2004) 40–56 www.elsevier.com/locate/brainres Review Afferent pain pathways: a neuroanatomical review

Tatiana F. Almeida*, Suely Roizenblatt, Sergio Tufik

Department of Psychobiology, Universidade Federal de Saõ Paulo, Rua Napoleaõ de Barros, 925. Vila Clementino, 04024-002, Saõ Paulo, SP, Brazil Accepted 23 October 2003

Abstract

Painful experience is a complex entity made up of sensory, affective, motivational and cognitive dimensions. The neural mechanisms involved in pain perception acts in a serial and a parallel way, discriminating and locating the original stimulus and also integrating the affective feeling, involved in a special situation, with previous memories. This review examines the concepts of nociception, acute and chronic pain, and also describes the afferent pathways involved in reception, segmental processing and encephalic projection of pain stimulus. The interaction model of the cerebral cortex areas and their functional characteristics are also discussed. D 2004 Elsevier B.V. All rights reserved.

Theme: Sensory systems Topic: Pain pathways

Keywords: Nociception; Afferent pain pathway; Tract; Supraspinal projection; Cortical structure

1. Introduction characterized as nociceptive pain. However, it is known that the painful phenomenon can occur spontaneously, as is the In 1986, the International Association for the Study of case for nonnociceptive pain represented by the reduction of Pain (IASP) defined pain as a sensory and emotional expe- the receptor thresholds due to alterations of the central rience associated with real or potential injuries, or described nervous system (CNS) [22]. There is a difference between in terms of such injuries. Pain has an individual connotation the terms nociception and pain; the first refers to the neuro- and suffers the influence of previous experiences [75]. This physiologic manifestations generated by noxious stimulus, definition takes into consideration the subjectivity of the while the second involves the perception of an aversive painful phenomenon and permits the understanding of im- stimulus, which requires the capacity of abstraction and the portant concepts concerning this subject. elaboration of sensory impulses [76]. Painful manifestations can be explained on the basis of According to the IASP definition, the relation between neural substrates mediating the sensory, affective, and pain and degree of injury is not obligatory. Thus, the alert nociceptive functions, as well as neurovegetative responses. function applies only to an acute manifestation, i.e., the one While the sensory, discriminative–perceptive component that follows damage to the tissue. Acute pain is character- permits the spatial and temporal localization, physical ized by the fact of being delimited in time and disappearing qualification and the intensity quantification of the noxious with the resolution of the pathological process. Chronic pain stimulus, the cognitive–affective component attributes emo- that persists for an extended period of time is associated tional coloring to the experience, being responsible for the with chronic pathological processes and causes suffering in behavioral response to pain [22]. multiple systems [75,79]. A noxious stimulus is capable of provoking a real or Knowing that pain represents a complex sensory modality potential injury, not necessarily causing pain. In this context, accompanied by affective, motivational and cognitive pain experienced by virtue of this type of stimulus is aspects, and also, associated with neurovegetative responses, this review provides neuroanatomical evidences of the neural pathways involved in the reception, processing, and trans- * Corresponding author. R. Vieira de Morais 601, ap: 116, Campo Belo, 04617-011, Sa˜o Paulo, SP, Brazil. Tel: +55-11-5539-0155; fax: +55- mission of the afferent nociceptive input because these 11-5572-5092. aspects are considered of fundamental importance for pain E-mail address: [email protected] (T.F. Almeida). perception.

2. Peripheral receptors of the A-Delta afferents. Their prolonged potentials undergo summation along time and induce the manifestations of dull The propagation of pain is initiated with the activation of pain. Although widely used, this differentiation does not physiological receptors, called nociceptors, widely found in apply to all organs, being more evident in the skin [22]. the skin, mucosa, membranes, deep fascias, connective The C-type fibers present thermosensitive receptors tissues of visceral organs, ligaments and articular capsules, reacting to heating and cooling, mechanoreceptors of low periosteum, muscles, tendons, and arterial vessels. The threshold and specific receptors for algogenic substances receptors correspond to free nervous endings and represent such as potassium ions, acetylcholine, proteolytic enzymes, the more distal part of a first-order afferent neuron consist- serotonin, prostaglandin, substance P, and histamine. Many ing of small-diameter fibers, with little or unmyelinated, of C fibers with high-threshold receptors respond equally to the A-Delta or C type, respectively. Their receptor fields can thermal and mechanical stimuli, or are sensitive to mechan- consist of areas ranging from punctiform regions to regions ical, thermal and chemical stimuli, and for this reason are measuring several millimeters in diameter, or even of more called, polymodal. A special type of C fiber respond to high than one site in distant territories [69,74]. intensity thermal stimuli and, in association with polymodal The nociceptors found in the skin originate from small fibers, seem to be responsible for the mediation of the flare nervous stems that, when approaching the epidermis, lose response after tissue damage. Another type of C fiber of their myelin, ramifying into extensive plexuses. Two types slow conduction, mechanoinsensitive, and mediated by of free nervous endings exist: the ramified ones originating histamine is also recognized and is probably involved in from 1 or 2 myelinated fibers forming intraepithelial termi- the burning sensation. Finally, a new class of fibers is nations and the nonencapsulated glomerular bodies, deriv- described having receptors that do not respond to noxious ing from a single unmyelinated fiber and organized in a stimuli in general, called silent receptors, which are activat- densely spiral manner below the epidermis or the mucosa. In ed only in the presence of inflammation [76,102]. other organs, this organization may vary because the type of The A-Delta fibers are classified into two groups. The propagated stimulation, the form of propagation, and the first one, type I, corresponds to fibers with high-threshold quality of the painful sensation depend on the receptor mechanoreceptors that primarily respond to mechanical nervous fiber complex and the innerved organ [76,102]. stimuli of high intensity and respond weakly to thermal or Normally, the painful sensation results from specific chemical stimuli and, after being sensitized, to harmful heat. activation of the nociceptors by mechanical, thermal, or Group II presents fibers with mechanothermal receptors for chemical stimulus, and not by the hyperactivity of other high temperatures (45–53 jC) and some receptors for sensory modality receptors. They present higher thresholds intense cold ( À 15 jC) and later sensitized to vigorous than the other receptors and respond progressively accord- mechanical stimuli at nonnoxious thresholds [76]. ing to the intensity of the stimulus. However, the sensitiza- In the muscle, the stimulus in both A-Delta and C fibers tion of the nociceptors causes reduction of the thresholds produces an aching sensation, without differentiation, which and, in some cases, spontaneous activity [74,76,102]. is less localized than cutaneous pain. The A-Delta fibers propagate innocuous mechanical, thermal and chemical stimuli, noxious stimuli typical of ischemia/hypoxia, and 3. Peripheral afferent fibers painful pressure, being recognized as polymodal type fibers. About one-third of these fibers present special receptors that First-order afferent fibers are classified in terms of signal the amount of effort performed by a muscle group, structure, diameter, and conduction velocity. C-type fibers inducing alterations in the blood flow and in respiration are unmyelinated, ranging in diameter from 0.4 to 1.2 Am process. The C-type fibers present the same polymodal and have a velocity of 0.5–2.0 m/s; A-Delta fibers are characteristics as the A-Delta fibers, but with a 50% higher barely myelinated, ranging in diameter from 2.0 to 6.0 Am proportion of fibers for ischemia/hypoxia and noxious and have a velocity of 12–30 m/s. The A-Beta fibers are pressure [76,102]. myelinated, with a diameter of more than 10 Am and a In visceral organs, the noxious and nonnoxious informa- velocity of 30–100 m/s, and do not propagate noxious tion is propagated by A-Delta and C fibers, and not by potentials in normal situations; however, they are funda- genuine A-Beta fibers [76]. Because electric stimuli of low mental in the painful circuitry because they participate in the intensity elicit vagal sensations of fullness and nauseas, mechanisms of segmental suppression [76,95]. while electric stimuli of high intensity cause pain, it is In the presence of a noxious stimulus, the primary believed that the visceral painful perception is dependent on nociceptive afferents show differentiated patterns of propa- the intensity of the stimulus. Additionally, the sparse orga- gation. The A-Delta fibers propagate modally specific nization of the receptors and their poor differentiation information, with marked intensity and short latency. They suggest that this perception also depends on spatial summa- promote a quick sensation of first phase or acute pain, tion. The sensations originating from the chest and abdomen triggering withdrawal actions. The C-type fibers propagate are propagated to the CNS by means of the sympathetic and information in a slower way, at times secondary to the action parasympathetic chains. The sensations of the abdominal 42 T.F. Almeida et al. / Brain Research 1000 (2004) 40–56 organs are poorly localized and are referred to distant of noxious and nonnoxious fibers, this group plays a regions from the affected area, different from those origi- fundamental role in the mechanisms of segmental suppres- nating from the chest, which can be directly located on the sion of pain involved in the Gate Control Theory [70]. They affected region because they are conducted directly by local are found in laminae I, II (external), IV, V, VI, X and in the spinal nerves [76,95]. anterior horn. Their main characteristic is the capacity of coding for the stimulus intensity because they show increas- ing frequencies of response from innocuous to noxious 4. Spinal cord stimulation. Their receptor fields are extensively organized in the more central regions of the dorsal horn and demon- The primary afferents reach the spinal cord and the brain strate variation of the activated area depending on stimulus stem, through the cranial nerve pairs V, VII, IX and X. intensity [76,92,101]. When approaching these structures, they detach from The NonNociceptive (N-NOC) neurons respond to in- thicker fibers, organizing themselves in the ventrolateral nocuous stimuli such as low intensity mechanical, thermal bundle of roots. They are part of the Lissauer Tract and form and proprioceptive ones, propagated by A-Delta and A-Beta synapses with second-order neurons distributed along the fibers. They are localized in laminae I, II (internal), II and dorsal horn of the spinal cord, organized according to the IV, and act indirectly in segmental suppression mechanisms Rexed laminae [75]. About one-third of the ventral roots are [76,92]. sensitive and predominantly painful, although their cell The interaction model of the afferent information in the bodies are located in the dorsal root ganglion. The integra- dorsal horn of the spinal cord (DHSC) proposes several tion with the neurons of the dorsal horn of the spinal cord pathways for the nociceptive impulses to reach the projec- occurs after the passage through the anterior horn or by the tion neurons and from there, the supraspinal structures. The fibers that, before penetrating in the ipsilateral anterior horn, WDR and SN in the superficial layers can be directly are directed to the dorsal horn [75,76]. activated by A-Delta or C fibers or through the activation Intrinsic neurons of the dorsal horn promote the interac- of the excitatory neurons that are located in lamina II tion of the afferent and efferent nociceptive stimuli, and are (external). The afference of nonnoxious potentials propa- also responsible for their transfer to supraspinal structures. In gated by A-Beta fibers that reach the WDR and N-NOC view of the reception and integration of the afferent stimulus, neurons in layers I and II (external) is provided by excit- they can be classified as projection neurons (PN) that directly atory neurons originating in deeper layers because these transmit the information to supraspinal centers, intersegmen- fibers do not innervate the superficial layers. In layer V, the tal propriospinal neurons (IPN), that integrate several spinal projection neurons receive direct afferences from C-type levels, and also to the ipsilateral and contralateral regions, fibers. However, they show dendrites that reach the super- initiating and mediating the descending inhibition with im- ficial layers, being indirectly stimulated by excitatory neu- plication in reverbatory mechanisms of sensitization; inter- rons of lamina II (external) [76,92]. neurons, that can be divided into interlaminar and Moreover, the WDR and N-NOC neurons are activated intrasegmental intralaminar types, the latter also having by A-Beta fibers and, in this case, they are important as inhibitory (INI) or excitatory (INE) characteristics [76]. relays for interaction of the noxious and nonnoxious stimuli. The neurons of the dorsal horn of the spinal cord present This model also takes into consideration the role of inhib- differentiations with respect to the type of sensitive conver- itory neurons in the modulation of the afferent impulses for gence, i.e., the type of afference they receive. They are the projection neurons. The inhibitory neurons are activated classified into three distinct groups and the organization of by A-Delta, C and A-Beta fibers and regulate the nocicep- the ascending pathways of the spinal cord and the response tive activity by interacting with the projection neurons and pattern in the presence of the nociceptive impulse depend on the primary afferents by presynaptic and postsynaptic inhib- them. The specific nociceptive neurons respond exclusively itions, respectively [76]. to noxious stimuli and they are found in laminae I, II (external), V and VI. The sources of input for these neurons are A-Delta nociceptive fibers of high threshold and heat 5. Afferent nociceptive pathways of the spinal cord nociceptive and C polymodal nociceptive fibers. Their receptive fields are punctiform and show somatotropic After the direct or indirect interactions with the projec- organization, mainly in lamina I. The specific nociceptive tion neurons in the DHSC, the axons of second-order neurons present a limitation for the gradual response to neurons become part of the constitution of the anterolateral different stimulus intensities but are involved in the codify- fascicle or posterior fascicle, forming afferent bundles that ing of the localization and physical quality of this stimulus transmit the nociceptive impulses to structures of the brain [76,92,101]. stem and diencephalon including the thalamus, periaque- The Wide Dynamic Range (WDR) neurons respond to ductal substance, parabrachial region, reticular formation of mechanical, thermal and chemical stimuli coming from the the medulla, amygdaloid complex, septal nucleus, and A-Delta, C and A-Beta fibers. Because of the convergence hypothalamus, among others [76,102]. T.F. Almeida et al. / Brain Research 1000 (2004) 40–56 43

The different ascending bundles form two phylogenetic thalamus involved in the affective component of the painful different systems. The first, older one, runs through the experience [95,112]. medial region of the brain stem, and is formed by the paleospinothalamic, spinoreticular, spinomesencephalic, spi- 5.2. Spinoreticular tract noparabrachio-amygdaloid, spinoparabrachio-hypothalamic, and spinohypothalamic bundles. The other system, more This tract originates mainly in laminae V, VII and recent, occupies the lateral region of the brain stem and VIII, and also in laminae I and X, mostly from SN and consists of the neospinothalamic bundle, spinocervical bun- WDR, although also involving N-NOC neurons, which dle, and postsynaptic beam of the dorsal horn [76]. propagate noxious and innocuous stimuli (Fig. 2) [50,60, 71,76,102]. 5.1. Spinothalamic tract The spinoreticular tract presents two projection components in the brain stem; one of them directed at the This tract originates from neurons of the WDR, SN precerebellar nucleus in the lateral reticular formation, and N-NOC types propagating innocuous and noxious involved in motor control, and the other directed to the potentials that are related to pain, temperature, touch and medial pontobulbar reticular formation involved in the itching [5,6,31,69,74,104]. In the medulla, the bodies of mechanisms of nociception [76]. Some fibers originating these neurons are located in larger numbers in laminae I and from lamina I reach the dorsal and ventral subceruleus V, but are also found in laminae II, IV, VI, VII, VIII and X nuclei, from which projections to the intralaminar nuclei (Fig. 1) [27,31,76,114]. of the thalamus, ventral thalamus and hypothalamus The lamina I neurons have been the subject of many [11,47,52,59,60,64,86,95,103]. However, the real functional studies. According to the morphology of the soma and the importance of this tract is believed to be due to the orientation of the dendrites, there are distinct fusiform, connections established in the brain stem because the pyramidal and multipolar cellular types, which probably projections to the intralaminar nuclei of the thalamus are form distinct physiological systems for the propagation of sparse and probably occur by means of collateral branches pain and temperature [111]. This concept is supported by the of the spinothalamic tract [50,70]. description of modally differentiated fibers in this lamina, The afferences of spinoreticular tract are involved in the exclusively activated by noxious cooling, and others with motivational–affective characteristic, as well as the neuro- specific nociceptive characteristic, which present different vegetative responses to pain [25,74,76,112]. This tract is an arrangements in the midbrain and project to distinct regions important pathway for the modulation of the nociceptive of the thalamus [28,41,46]. segmental pathways by activating brain stem structures Still in lamina I, SN neurons receive inputs from A-Delta responsible for descending suppression [35,50,70,112]. fibers of high threshold for mechanical and thermal stimuli. The WDR neurons receive afferences from fibers of non- 5.3. Spinomesencephalic tract noxious high threshold in general and also inputs from C- type fibers [76,78]. With respect to noxious mechanical The neurons that give origin to this tract are WDR, SN stimuli, SN neurons are classified as maintenance cells and N-NOC and are arranged in the spinal cord in a manner because they exhibit a prolonged response time in relation similar to the neurons of spinothalamic tract, obeying a to the initial stimulation. In contrast, the WDR are classified somatotopic organization, mainly in laminae I, II, IV, V, VI, as adaptive neurons because their time response ends right but also observed in laminae VII, X, and in the ventral horn after the end of the initial stimulus. Only the SN have the (Fig. 3) [26,54,72,76,100,102,108–110]. Fibers originating ability to code the intensity of the stimulus and are possibly in lamina I, in the region of the cervical intumescence, and responsible for the sensation of pain caused by sustained at some thoracic levels show two distinct afferent systems, mechanical stimuli, also contributing to the acute sensation ipsilateral and bilateral, occupying the dorsolateral funiculus of pain [7,102]. [54,71,100,109,110]. According to the site of their projec- Based on the origin and the model of projection of these tions, two systems of different afferences are considered. fibers, some authors have described three forms of affer- The spinoannular bundle, that projects to the periaqueductal ences of the spinothalamic tract. One is the monosynaptic gray (PAG) matter, and the spinotectal bundle that reaches neospinothalamic pathway or ventral spinothalamic tract, the deep layers of the superior colliculus [72,76]. that directly projects to nuclei of the lateral complex of the The projections to the midbrain periaqueductal gray thalamus, involved in the sensory–discriminative compo- (PAG) matter originate from WDR and SN, and are func- nent of pain. Another is the multisynaptic paleospinothala- tionally distinct. Those that reach the PAG in the portion mic pathway, or dorsal spinothalamic tract, that projects to more dorsal to the limiting sulcus have an excitatory nuclei of the posterior medial and intralaminar complex of characteristic in afferent nociceptive transmission and those the thalamus, involved in the motivational–affective aspects that project more ventral to the limiting sulcus activate of pain. Finally, a monosynaptic spinothalamic pathway inhibitory mechanisms responsible for the inhibition of the projecting directly to the medial central nucleus of the afference of this same pathway. A pattern of excitation 44 T.F. Almeida et al. / Brain Research 1000 (2004) 40–56

Fig. 1. Spinothalamic tract. Most of the axons decussate transversely through the anterior white comissure of the spinal cord and ascend through the lateral contralateral funiculus; some of them show an ipsilateral course [49,76,80,98,114]. During its passage through the brain stem, the spinothalamic tract originates collateral branches destined to the reticular formation of the medulla, pons and midbrain, including the gigantocellularis and parogigantocellularis nuclei and periaqueductal gray matter, probably responsible for the activation of the descending suppressor system, the behavioral response and also the neurovegetative responses to pain [76,112]. T.F. Almeida et al. / Brain Research 1000 (2004) 40–56 45

Fig. 2. Spinoreticular tract. Along the tract, most of the fibers run through the anterolateral funiculus, together with the ventral spinothalamic tract. The afference originating in the laminae from the lumbar intumescence is mainly contralateral; although a portion originating in laminae I and V ascends in an ipsilateral manner. The afferences originating in the cervical intumescences and sacral segments are arranged bilaterally in the direction of the brain stem [40,50,60,72,76,102,110]. The main structures innervated by this tract are: nucleus raphe magnus, retroambiguous nucleus, supraspinal nucleus, medulla central nucleus, lateral reticular nucleus, gigantocellularis nucleus, parogigantocellularis nucleus, pontine caudal and oral nucleus, in addition to the parabrachial region. followed by inhibition is commonly observed when stimu- tract has also been described in cervical, thoracic and lating the PAG, as well as other regions of the midbrain. lumbar segments that activate one another in the direction This suggests an autoregulatory medullary/midbrain activity of the PAG and of the ventroposterolateral nucleus of the with different connections and velocities of propagation thalamus [103]. [42,106,107]. In addition to the characteristics of somatosensory pro- The activity of spinomesencephalic tract, as well as the cessing and activation of the mechanisms of descending spinothalamic tract and the postsynaptic route of the dorsal analgesia, the stimulation of regions innervated by the column, suffers inhibitory or excitatory influence from spinomesencephalic tract produces different responses impli- interneurons activated by collateral neurons of the spinocer- cated in nociceptive processing. Thus, stimulation of these vical tract [38,39]. A model of collateralized afference regions is capable of provoking aversive behaviors in the between the spinomesencephalic tract and spinothalamic presence of noxious stimuli and motor responses of the visual 46 T.F. Almeida et al. / Brain Research 1000 (2004) 40–56

Fig. 3. Spinomesencephalic tract. Most of the fibers ascend through the anterolateral contralateral funiculus of the spinal cord, together with the ventral and spinoreticular spinothalamic tract, although some have been detected in the dorsolateral funiculus. Studies with anterograde tracers and techniques of neuronal degeneration have indicated that the main structures of projection of spinomesencephalic tract are the lateral and ventrolateral region of the PAG, the posterior pretectal nucleus and the Darkschewitsch nucleus. Moderate projections to the medial region of the PAG, cuneiform nucleus and midbrain reticular formation, the lateral region of the deep laminae of the superior colliculus and the medical magnocellular nucleus. Lesser projections to the most dorsal region of the PAG, nucleus of inferior colliculus, the intermediate lamina of the superior colliculus, the lateral region of the red nucleus and in the Edinger–Westphal region of the oculomotor nucleus, besides scarce fibers projecting to the interstitial nucleus of Cajal and anterior pretectal nucleus [100,106,107]. Projections from neurons of lamina I occur solely towards the medial region of the thalamus or towards the thalamus and midbrain [110]. desertion type, besides autonomic, cardiovascular, motiva- propagation of visceral pain due to the inflammatory process tional, and affective responses [42,54,55,76,106,108,110]. and thermal stimuli at noxious levels [9,17,56,101,111]. The PN receives afferences from the spinomesencephalic 5.4. Spinoparabrachial tract tract, the sacral parasympathetic nucleus and collaterals of the spinoreticular tract. It projects to the thalamus and to the The parabrachial nucleus (PN) receives direct and indi- spinal cord, in addition to the structures described above rect afferences from nociceptive pathways. The neurons of [76,86]. However, the afferences to the amygdala and other laminae I and II of the SN neurons participate in the direct limbic structures do not occur exclusively through the PN. afferences, representing a genuine nociceptive pathway Direct tracts from the spinal cord to the amygdala, lenticular (Fig. 4) [9,10,76,92,101]. nucleus, nucleus accumbens, septum, cingular, frontal and The collaterals of other afferent tracts that converge to the infralimbic cortex have been described. For this reason, they PN constitute the indirect nociceptive pathways [112]. Studies are considered spinal–limbic pathways by some authors have demonstrated that these two pathways are involved in the (Fig. 4) [37,48,92,102,111]. T.F. Almeida et al. / Brain Research 1000 (2004) 40–56 47

Fig. 4. Spinoparabrachial tract. The axons of these neurons ascend through the contralateral dorsolateral funiculus up to the brain stem where, after reaching the NPB in its mesencephalic and pontine portions, give origin to two differentiated systems: the spinoparabrachial amygdaloid pathway and the spinoparabrachial hypothalamic pathway [76,92,101,111]. The spinoparabrachial amygdaloid pathway projects to the amygdala and stria terminalis from the NPB. The spinoparabrachial hypothalamic pathway projects to the ventromedial nucleus of the hypothalamus.

In view of the projection towards the first relay in the PN and N-NOC neurons. These neurons respond to noxious and and the formation of the two systems of afference to the innocuous stimulation coming from muscles, tendons, amygdala and hypothalamus, the function of autonomic, joints, skin and viscera (Fig. 5) [56,58,76]. motivational and affective regulation is attributed to the The pathway of its fibers constitutes an exception when spinoparabrachial tract, as well as the neuroendocrine compared to other tracts. Projections to the lateral, preforn- responses to pain [76,92]. ical, dorsomedial, suprachiasmatic and supraoptic nuclei have been described in the hypothalamus. It has been sug- 5.5. Spinohypothalamic tract gested that integration with the autonomic nervous system occurs starting from these regions by means of afferences to This structure originates from laminae I, V, X, the lateral the vagal dorsal nucleus and preganglionic neurons of the spinal nucleus, nucleus caudalis and some regions around intermediolateral column. During the afference to the brain the central medullary canal, and is composed of SN, WDR stem and diencephalon, collateral projections to the superior 48 T.F. Almeida et al. / Brain Research 1000 (2004) 40–56

Fig. 5. Spinohypothalamic tract. Many of these fibers travel along the contralateral anterolateral funiculus. After projection to nuclei of the lateral hypothalamus, approximately half of its fibers become part of the constitution of the supraoptic decussation, reach the ipsilateral hypothalamus and are directed caudally to innervate the thalamus, amygdala, septum, and striatum [33,66,107,108]. Current studies demonstrate that the activation of the thalamus precedes the projection of the spinothalamic tract to the hypothalamus [113]. colliculus, substantia nigra, red nucleus, pretectal nucleus, motivational–affective, and alert responses of somatic and globus pallidus, caudate–putamen and substantia innominata visceral origin of the painful experience [56,57,76,102, have been described (Fig. 5) [18,32,33,66]. The afferences to 113,115]. the hypothalamus are organized in different manners, the nonnociceptive potentials are propagated directly through the 5.6. Spinocervical tract trigeminal–hypothalamic tract and the nociceptive signals travel along two parallel pathways, the trigeminal–hypotha- This tract originates mainly from laminae III and IV, and lamic and reticular–hypothalamic tract [62,113]. to a lesser extent from laminae I, II and V. Its neurons The model of afferences of this tract suggests that its receive afferences from peripheral A-Delta and A-Beta projections can contribute to the neuroendocrine autonomic, fibers and mostly consists of WDR and N-NOC fibers, T.F. Almeida et al. / Brain Research 1000 (2004) 40–56 49 although SN have also been described (Fig. 6) [13,14,20, vical tract/spinal solitary tract system has been proposed, 27,43,76]. with a function in the integration of somatic and visceral Studies with anterograde and retrograde markers or stimuli. Similarly, neurons originating in laminae III, IV and neuronal degeneration have indicated that differentiated V, stimulated by A-Beta and A-Delta primary afferents, fiber systems originate from laminae III and IV in the form the spinocervical afferent system, the postsynaptic spinocervical tract. Cell groups in these laminae, stimulated pathway of the spinal column, from collaterals that at the by A-Delta fibers, originate projections to the lateral cervi- level of the cervical–thoracic junction project towards the cal nucleus and the solitary tract nucleus and receive lateral spinal nucleus and the nucleus of the spinal column descending projections from these structures. A spinocer- by means of the dorsolateral funiculus and the spinal

Fig. 6. Spinocervical tract. The pathway of the axons runs ipsilaterally from the dorsolateral funiculus adjacent to the spinocerebellar tract. Collaterals originate in the initial segment, travel over short distances in the spinal cord. Because it represents a multisynaptic pathway, it reaches the lateral cervical nucleus in the medullary segments C1–C3, the site of the first relay, from which it crosses the midline, becomes part of the constitution of the medial lemniscus and establishes second order projections with nuclei of the posterior and medial complex of the thalamus. Collaterals have also been described for the midbrain in the PAG and superior colliculus, as well as with nuclei of the spine, medial spinal nucleus and from the lateral cervical nucleus directly to the spinal cord [54,76,102,106,109,110]. 50 T.F. Almeida et al. / Brain Research 1000 (2004) 40–56

Fig. 7. Postsynaptic pathway of the spinal column. It is organized into a multisynaptic pathway running along an ipsilateral course in the spinal cord up to the first relay in the nucleus of the spinal column, projecting through the medial lemniscus towards the lateral complex of the thalamus and the superior colliculus, in addition to originating collaterals in the spinal cord itself [51,79,98].

column, which are modulated at these levels by descend- nucleus. Afferent fibers of the spinocervical tract originating ing inhibitory projections and by the action of local from laminae I, III, IV and V in the cervical and lumbar interneurons [29,44,45,65,68,83,100,113]. Other collaterals segments reach differentiated neurons in the medial region have also been described, suggesting the activation of the that serve as the basis for the inhibition of the lateral spinal spinomesencephalic, spinothalamic, spinocervical and spi- nucleus [29,50]. The functions related to this tract concern the noreticular tracts from the stimulation of the spinocervical sensory–discriminative, motivational–affective and auto- tract [20,38,39,45,46,54,115]. nomic characteristics of pain, as well as a role as sensory Apparently, the medial spinal nucleus exerts an inhibitory integrator and modulator of afferent inputs in the spinal cord modulation by means of collaterals on the lateral spinal [46,67,76,110]. T.F. Almeida et al. / Brain Research 1000 (2004) 40–56 51

5.7. Postsynaptic pathway of the spinal column convergence of fibers and the function of these nuclei occur from the projections of spinothalamic tract. Thus, it was This structure originates mainly from laminae III and V, demonstrated that neurons of the WDR type predominate in also occurring in laminae VI and VII. It consists of neurons the VPL and VPM nuclei, and that SN neurons are found in of the WDR, SN and N-NOC, from which groups of fibers the VPI nucleus. They all respond to the thermal and are organized along two distinct pathways, close to the mechanical stimuli, and some also respond to freezing. midline of the spinal cord and at the junction of the gracile Although they show a somatotopic organization, the receptor and cuneiform bundles originating from the lumbar–sacral fields in VPI nuclei are larger than those in the VPL and VPM region and the thoracic column, respectively (Fig. 7) nuclei, and are characterized by a punctiform aspect. More- [2,51,76,79,98]. over, their projections to the SII cortex suggest different Extensive direct and indirect projections are described for forms of processing with respect to the sensory–discrimina- the gracile nucleus, which plays an important role of sensory tive and affective–cognitive aspects of pain [8,73,76,83,97]. integration of the projections from abdominal organs and The VPL nucleus is recognized as the main somatosensory from the skin, and then projecting to the thalamus [1,3,23,76]. relay. The convergence of noxious and innocuous stimuli of The postsynaptic pathway of the dorsal column represents cutaneous, muscular, and articular origin has been demon- the largest afferent pathway for information of visceral origin, strated in several studies [24,55,63,82,99] as well as inter- as determined in studies that demonstrated the control of connections with the primary somatosensory (SI) cortex, visceral cancer pain by means of myelotomy techniques, responsible for the aspects of pain localization and intensity limited myelotomy to the midline [51] and corroborated by [53,89,99,101,104]. However, neurons have been described similar findings after injuries or administration of morphine which equally respond to the somatic and visceral stimuli in to rats and monkeys into the pathway of the spinal column addition to specific visceral neurons, showing that this [2]. Injuries in this region have proved to be more effective in nucleus also participates in the processing of visceral pain the control of visceral pain than interruption in the pathway of [15,114] which occurs through the postsynaptic pathway of the anterolateral quadrant [1,4,76,79]. This pathway also the dorsal column with projections for the gracile nucleus presents functions related to kinesthesia, discrimination be- [1,76,79]. Visceral afferences of the spinothalamic tract have tween two points, and graphesthesia. In view of the regions of also been described, although their main noxious conver- thalamic projection, the postsynaptic pathway of the dorsal gence originates from the skin [22,81]. These two systems column is considered to be involved in the sensory–discrim- seem to contribute discriminative aspects of visceral pain inative and motivational–affective components of pain [16,98]. The VPM nucleus presents cell types and organiza- [1,76]. tion similar to the VPL nucleus, being similarly involved in the sensory–discriminative [104] aspects of thermal, mechanical and tactile information [14,66,104]. However, its 6. Afferent supraspinal projections of the nociceptive contribution to the painful experience is differentiated. By pathway virtue of its projections to the prefrontal cortex, the convergence of fibers originating from the parabrachial region and From the interaction of the sensory impulses in the spinal the paratrigeminal nucleus, together with the interconnec- cord, the nociceptive afferent pathways give origin to the tions with the amygdala, hypothalamus and PAG, suggests an different models of projection to subcortical and cortical involvement in the emotional aspects, psychomotor and structures. In this stage, the sensory–discriminative and autonomic responses of pain [21,48,66,77]. affective–cognitive components referring to the painful ex- The existence of inhibitory interactions involving VPL perience are attributed to the nociceptive impulse. Studies and VPM nuclei, which form a modulatory system similar have indicated that the midbrain, thalamus, hypothalamus, to that presented in the Gate Control Theory [70] in the lentiform nucleus, somatosensory cortices, insular, prefron- propagation of pain to superior centers is well known tal, anterior and parietal cingulum are basic structures in this [94,97,98]. Other afferences to the lateral complex of the circuitry [19,34,36,59,78,85,91,103]. thalamus include fibers of the spinocervical tract [13], spinoparabrachial tract [48], and spinoreticular tract [60,93]. 6.1. Thalamus The posterior complex of the thalamus consists of the pulvinar oralis nucleus, posterior nucleus (PO), and the The thalamus represents the main relay structure for sen- posterior division of the ventromedial nucleus (VmPO). It sory information destined to the cortex and, involved in the presents sparse receptor fields without a somatotopic orga- reception, integration, and transfer of the nociceptive poten- nization and is organized in a reverberating cortical–tha- tial. The different projections to its nuclei and from them to the lamic–cortical circuitry, which strengthens the activation of cortex define the functional circuitry of pain processing [76]. thalamic and cortical neurons in the presence of the noxious The lateral nuclear complex consists of the ventropostero- stimulation [76,90]. lateral (VPL), ventroposteromedial (VPM) and ventroposter- The VmPO and PO nuclei are an integral part of the oinferior (VPI) nuclei. Studies have shown that the medial nociceptive system, establishing connections with 52 T.F. Almeida et al. / Brain Research 1000 (2004) 40–56

Fig. 8. Nociceptive thalamic efferences to cortical and subcortical regions. Lateral nuclear complex: ventroposterolateral (VPL), ventroposteromedial (VPM), ventroposteroinferior (VPI) nuclei. Posterior nuclear complex: posterior nuclei (PO), posterior division of the ventromedial nucleus (VmPO). Medial nuclear complex: ventral region of the dorsal medial nucleus (MDvc), centromedial nucleus (CM), lateral central nucleus (LC). the insular and cingular cortex and are involved in the Spinoreticular projections have been described for this affective–cognitive aspects of pain [84,97]. Specific pro- nucleus [60,74,101]. However, the subject remains contro- jections of the spinothalamic tract originating from lamina I versial [11]. Similarly, projections of the spinomesence- indicate that these nuclei are centers of integration of painful phalic tract [110] and spinohypothalamic tract have been and thermal noxious information, mainly in the presence of described (Fig. 8) [107]. freezing and visceral sensations [12,46,61,108]. Spinotha- lamic projections to the PO nucleus have been described 6.2. Cortical projections from the superficial and also from the deeper laminas of the dorsal horn, in the region of the cervical intumescence. Considering the multiple aspects of the painful experi- Neurons in this region respond to the noxious and innocu- ence, the models of afference to thalamic nuclei and their ous mechanical stimuli, showing representations of some cortical projections, two systems of nociceptive projection corporal regions [107]. acting in a parallel and complementary manner are distin- In addition to the spinothalamic tract, the posterior guished, i.e., the lateral and medial systems. Within this complex of the thalamus receives afferences from the perspective there are three important cortical regions which spinohypothalamic tract [107] spinoparabrachial tract [12], have been studied on the basis of functional criteria by and postsynaptic pathway of the dorsal column [76]. The means of single neuron recordings: primary somatosensory medial complex of the thalamus is composed by the ventral cortex (SI), secondary somatosensory cortex (SII), and the region of the dorsal medial nucleus (MDvc) and by the anterior cingulated cortex [8,76,83,96,97,105]. intralaminar nuclei, among them, the lateral central nucleus The lateral system participates directly in the sensory– (LC) and the centromedial nucleus (CM). Extensive recep- discriminative attribution of nociception and involves spe- tor fields are described—bilaterally activated and projecting cific thalamic nuclei, which project to SN and WDR neurons to the cingular cortex [82] suggesting a contribution to the of the SI and SII cortices. The ability to code topographically motivational–affective aspects of pain [74,101,102,110]. noxious stimuli of different intensities is a predominant Like the VmPO nucleus, it receives afferences from laminae function of the nociceptive neurons present in SI I and V of the spinothalamic tract [30,60,82,97,105] and [89,99,101,104]. Although SN and WDR neurons are able interconnects with structures responsible for the control of to code the intensity of these stimuli, this function seems to be attention and motor response, such as the striatum and the related more to the WDR type whereas SN neurons mainly cerebellum, probably involved in the escape behavior in the act on the topographic localization of peripheral stimuli. This presence of a harmful stimulus [76]. characteristic may indicate that both the localization of the

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