5 Mechanisms of Somatic Pain

William D. Willis, Jr.Department of Anatomy and Neurosciences, Marine Biomedical Institute,University of Texas Medical Branch, Galveston, Texas 77555 Pain that originates from the limbs and the body wall is signaled by a neural system, the pain system (88), that includes nociceptors, a processing circuit in the dorsal horn, several parallel ascending tracts, and higher-level processors in several regions of the brain, including the thalamus and the cerebral cortex. The emphasis here will be on the initial stages of the pain system, including the nociceptors and the dorsal horn. In addition, reference will be made to changes in the initial processing of nociceptive signals that result from pathological events.

SOMATIC NOCICEPTORS Cutaneous Nociceptors

Several types of cutaneous nociceptors can be distinguished on the basis of the size and state of myelination of their primary afferents and their responsiveness to various kinds of noxious stimuli (88,89). The most prominent types in mammals, including primates, are (i) A mechanical nociceptors (71); (ii) A mechanoheat nociceptors (28,46); and (iii) C polymodal nociceptors (6). However, several less common varieties have been recognized (6), and a new class of chemical nociceptor has recently been proposed (2). A nociceptors are supplied by small myelinated axons that conduct in the range of 4 to 44 m/sec (median, 9.3 m/sec) (28). A mechanical nociceptors are normally responsive just to intense mechanical stimuli and not to noxious heat or chemical stimuli (71). However, they can be sensitized by noxious heat, after which they respond to later heat stimuli (26). On the other hand, A mechanoheat receptors respond not only to intense mechanical stimuli but also to noxious heat, even on the first exposure to such a stimulus (28). C nociceptors are supplied by unmyelinated axons that conduct at about 0.5 to 1 m/sec (6). C polymodal nociceptors can be activated by noxious mechanical, thermal, or chemical stimuli (6). However, in experimental work, they are generally recognized by their responses to both noxious mechanical and heat stimuli, and some authors prefer to call them C mechanoheat nociceptors (43). Other C nociceptors have been recognized that have restricted sensitivity to noxious mechanical and sometimes to cold stimuli (6). Recently, it has been recognized that some primary afferent fibers in cutaneous nerves do not respond to any of the stimuli normally employed to activate sensory receptors (30,54). These normally ``silent nociceptors'' can be sensitized by noxious events, after which they become responsive to noxious mechanical and thermal stimuli. Such nociceptors may in fact be chemical nociceptors that respond to the chemical products released during the course of inflammation (2).

Articular Nociceptors
Joint nerves contain about twice as many unmyelinated afferent axons as myelinated ones (48). For joint and muscle nerves, the nomenclature is different than for cutaneous nerves. Group III afferent fibers are small myelinated axons and group IV unmyelinated axons. Many fibers in both size ranges with receptive fields to local mechanical stimulation respond best or only to strong rotation of the joint into the noxious range (74,75). Some joint nociceptors are normally silent with respect to joint movements; however, they can be sensitized by inflammation, after which they respond even to slight movements of the joint (76).

Muscle Nociceptors
Fine muscle afferents in groups III and IV ranges also appear to serve as nociceptors (59). They respond to mechanical, thermal, and chemical stimuli (40,57,58), and some group IV muscle afferent fibers are activated more strongly during muscle ischemia (60). It is likely that a subgroup of fine muscle afferent fibers are ergoreceptors, rather than nociceptors (57). Ergoreceptors signal the workload of the muscle.

Somatic Nociceptors and Pain Quality

Different types of somatic nociceptors signal different qualities of pain. This has been shown by experiments on human subjects using macro- or microstimulation of peripheral nerve fibers. The qualities of cutaneous pain include pricking pain and burning pain (51). These are characteristic, respectively, of the first and second pain sensations that arise from intense stimulation of certain areas of the body, such as the feet or hands (52). Pricking pain is elicited when a cutaneous nerve is stimulated electrically at an intensity that activates A fibers; burning pain is produced when such a stimulus also activates C fibers (55,81). Burning pain is also felt during stimulation when the A fibers in a peripheral nerve are blocked. Furthermore, microstimulation of C fibers through a microneurography electrode evokes burning pain (67). The distinction between first pain and second pain can only be made in areas distal enough from the central nervous system that the volleys in A[sp[fy20,2]e[rp and C fibers arrive separately in time (52). Muscle pain has an aching quality. Aching pain can be elicited by stimulation of a muscle nerve in human subjects (83).

Sensitization
An important point of distinction between nociceptors and other types of somatic receptors is that repeated or strong stimulation tends to cause fatigue of most types of receptors (8) but may sensitize nociceptors (6). Sensitization of nociceptors can be produced by exposure of the nerve terminals to any of several chemical substances known to be released in somatic tissues by noxious stimuli, including prostaglandins, bradykinin, serotonin, and histamine (3,14,29,47). Sensitized nociceptors become more responsive to previously effective stimuli. They discharge more in response to a given stimulus intensity, and they develop a lower threshold

(6,46,62). Furthermore, they may become responsive to new forms of stimulation. For example, it was mentioned earlier that A mechanical nociceptors are normally responsive only to intense mechanical stimuli. However, after sensitization by a cutaneous burn, A mechanical nociceptors become responsive to noxious heat (26). It has been proposed that sensitized nociceptors are responsible for primary hyperalgesia (45,46,62). Primary hyperalgesia is distributed in the area of damage and is an increase in the pain provoked by a particular type of noxious stimulus following damage (31). Other forms of noxious stimuli may become more effective, and the pain threshold may also be lowered. For example, when the skin undergoes a mild burn, primary hyperalgesia for both mechanical and thermal stimuli may develop. Under some experimental conditions, this is best explained by sensitization of A mechanical nociceptors (62). Under other experimental conditions, sensitization of C fibers contributes to the primary hyperalgesia (45).

PROCESSING OF NOCICEPTIVE SIGNALS IN THE DORSAL HORN Terminations of Nociceptors

The primary afferent fibers supplying cutaneous nociceptors reach the spinal cord through the dorsal roots. A[sp[fy20,2]e[rp nociceptors terminate in the superficial dorsal horn (laminae I and II), the neck of the dorsal horn (lamina V), and in the gray matter surrounding the central canal (lamina X) (53). C nociceptors terminate chiefly in the substantia gelatinosa (lamina II) (79). Most of the terminals of fine articular and muscle afferent fibers are in the marginal zone (lamina I), although some also end in lamina V (15,16). Fine somatic afferent fibers are characterized by the presence in their terminals of peptides, such as substance P (SP) and calcitonin gene-related peptide (CGRP) (11,20,34,85). The peptides are associated with dense-cored vesicles. The same nerve endings also contain clear, round vesicles that appear to contain an excitatory amino acid (EAA) transmitter, such as glutamate (19,61). It is thought that activity in nociceptive afferent fibers will release the EAA neurotransmitter to effect rapid excitatory synaptic transmission and, under some circumstances, one or more peptides that then modulate later synaptic transmission. The terminals of somatic nociceptors synapse on both excitatory and inhibitory interneurons and also directly on ascending tract cells, such as spinothalamic tract (STT) neurons. One way in which these connections have been demonstrated is by use of immunocytochemical markers, such as CGRP. In the dorsal horn, CGRP appears to be restricted to primary afferent fibers (13,84,85). Therefore, synaptic terminals containing CGRP, as demonstrated by immunocytochemistry at the ultrastructural level, can be considered primary afferent terminals. CGRP-containing synapses have been described in contact with dorsal horn neurons that contain inhibitory amino acids (presumed inhibitory interneurons; ref. 32), as well as with projection cells (66), including identified STT cells (12).

Responses to Noxious Stimuli

The central effects of signals transmitted by nociceptors include activation of both excitatory and inhibitory circuits. The excitatory events lead to transmission of nociceptive signals to

higher centers by ascending tract cells, such as STT neurons. On the other hand, inhibitory events limit those discharges, shape the receptive fields of nociceptive neurons at all levels of the pain system, and provide opportunities for therapeutic interventions. Inhibitory circuits are found both in the dorsal horn and in supraspinal control systems activated by discharges in ascending tracts. The local inhibitory circuits presumably involve interneurons that contain inhibitory amino acid neurotransmitters (10,72). Peptides are also likely to contribute to inhibitory events in the dorsal horn. Candidate inhibitory peptides present in dorsal horn neurons include the opioid peptides, enkephalin and dynorphin (35,41,64,80). Inhibitory substances in the terminals of descending control systems include serotonin and norepinephrine (42,63,86,87). Descending excitatory pathways can also produce inhibition by activation of inhibitory interneurons in the dorsal horn. Because of this inhibitory circuitry, ascending tract cells, such as STT neurons, have inhibitory (as well as excitatory) receptive fields (29). The most powerful inhibition of STT cells is produced by noxious stimulation of the skin in areas separate from the excitatory receptive field. Much of the inhibition remains after transection of the spinal cord and so depends on inhibitory circuitry in the dorsal horn (29). However, some of the inhibition arising from the inhibitory receptive field depends on supraspinal circuits, perhaps like those responsible for the ``diffuse noxious inhibitory controls'' described by Le Bars and colleagues for dorsal horn neurons in general (49,50). The inhibition in this case depends on the activation of the ``endogenous analgesia system'' (89). Inhibition of nociceptive dorsal horn cells can also result from activation of mechanoreceptors (92). This is the type of inhibition that led to the Gate Control Theory of Melzack and Wall (56). This inhibition probably depends on dorsal horn inhibitory interneurons.

Responses of STT Cells

Pain signaling requires that information from nociceptors be transmitted from the dorsal horn to higher centers for processing and interpretation. The information is carried by a number of ascending tracts, including the STT. It seems likely that the part of the STT that projects to the ventroposterolateral (VPL) nucleus of the thalamus in primates, including humans, is critical for the sensory discriminative aspects of pain (88). Motivational-affective aspects of pain are probably transmitted by the STT projections to the medial thalamus, as well as by the spinomesencephalic (SMT), spinoreticular (SRT) and other ascending tracts. Evidence that STT cells that project to the VPL nucleus signal the sensory discriminative aspects of pain comes from experiments in which the activity of STT cells in experiments can be correlated with human sensation. For example, the transient responses of primate STT cells to graded intensities of mechanical and thermal stimulation of the skin parallel the duration and intensity of pain provoked in human subjects (36,90). Similarly, intradermal injection of capsaicin causes a prolonged activation of STT cells (78), paralleling the prolonged pain sensation that is produced by similar injections in humans (43,44). The ability to localize the source of a painful stimulus applied to the skin can be explained by the small receptive fields of at least some STT cells, especially those in lamina I of the dorsal horn (25). A contribution to pain localization could also be made by concurrently activated mechanoreceptors.

Pain that originates from deep tissues, such as muscle or the viscera, is often subjectively referred to the body wall (33). Several explanations for this have been offered, but the most attractive seems to be the convergence of afferent input from nociceptors in the body wall and in deep tissue onto the same dorsal horn neurons (73). A number of studies have shown that STT cells receive a convergent input from muscle or viscera and from the skin. For example, STT cells in the upper thoracic spinal cord can be activated by stimulation of the left upper extremity and left side of the chest, as well as by activation of cardiopulmonary nociceptors (7). Similarly, STT cells in the upper lumbar spinal cord can be excited by stimulation of the flank and also of the testicle or urinary bladder (65). The receptive fields match well-known areas of distribution of the referred pain originating from such organs as the heart, testicle, and bladder (33).

ALTERATIONS IN NOCICEPTIVE PROCESSING BY INJURY OR INFLAMMATION Enhanced Responses Following Injury or Inflammation
The responses of STT cells can be shown to increase following cutaneous damage, provided that the damage is severe enough (68). For example, the STT cell in figure 1 was initially almost unresponsive to innocuous brushing of the skin (BR) in its excitatory receptive field (Fig. 1A, right), and there was a graded response to a graded series of compressive stimuli (PRESS, PINCH, SQUEEZE). After the same stimuli were applied repeatedly, causing progressive injury, the STT cell became responsive to the BR stimulus, and its responses to the weaker two compressive stimuli increased (Fig. 1B, right). These events reflected changes in the responses to stimuli applied to the damaged area. However, in addition, the STT cell became responsive to BR applied to undamaged skin (compare Fig. 1A, left, and B, left). Similar changes occur when the skin is damaged by noxious heat (37). For example, in Figure 2 , a series of STT cells responded in a graded fashion to innocuous indentations of the skin, using a controlled mechanical vibrator. After the skin was damaged by noxious heat, the responses to the indentations of the skin were increased, whether the stimulus was applied to the damaged skin (Fig. 2A) or to an undamaged area 1 cm away (Fig. 2B). Intradermal injection of capsaicin can have a comparable effect on the responses of STT cells to mechanical stimuli (24,78). For example, in Figure 3 , the responses of an STT cell to innocuous and noxious intensities of mechanical stimuli are shown to increase following an injection of capsaicin into the skin well away from the sites tested (in Fig. 3, compare parts C, E, and G with D, F, and H ) . Responses to noxious heat applied near the injection site are also increased and the threshold lowered (78). The same kinds of changes produced in these experiments by damage to the skin can also result during the course of acute experimental arthritis (23). For example, in Figure 4 , the responses of an STT cell to flexing the knee and to mechanical stimulation of the skin are shown before

and after injection of the knee joint capsule with kaolin and carrageenan. As the inflammation developed, the STT cells began to respond to knee flexion, its responses to stimulation of the cutaneous receptive field on the foot increased, and the cutaneous receptive field expanded. The alterations in the response properties of primate STT cells that result from skin damage or the induction of inflammation appear to parallel the development of primary and secondary hyperalgesia in humans subjected to comparable pathological events. Skin damage causes primary and secondary hyperalgesia (31,51). The primary hyperalgesia is restricted to the damaged area and is characterized by an increase in responses to noxious mechanical and thermal stimuli and a lowered heat pain threshold (43,44). The secondary hyperalgesia is characterized by an increased pain following noxious mechanical stimuli and a mechanical allodynia, but no change in the sensation produced by noxious heat stimuli (44,83). These are exactly the characteristics of the changed responses of primate STT cells following intradermal injection of capsaicin (24,78). Elements of this same picture are found in experiments involving mechanical and thermal damage of the skin, as well as experimental arthritis. Secondary hyperalgesia was attributed by Lewis (51) to sensitization of a previously undescribed system of ``nocifensor axons'' in the skin. However, tests of the responsiveness of nociceptors supplying the skin in the area of secondary hyperalgesia caused by intradermal injection of capsaicin fail to show any changes (2,43). Instead, secondary hyperalgesia appears to be due to a sensitization of central nociceptive neurons, as proposed by Hardy et al. (31). Evidence that primate STT cells are sensitized at a time when secondary hyperalgesia would occur in humans comes from two kinds of experiments. In one set of experiments, the responses of the STT cells to volleys in large dorsal root axons were shown to increase (78), and in the other set the responses to iontophoretically released excitatory amino acids (EAAs) were enhanced (24). In the latter study, the time course of the increased responses was shown to resemble that of secondary hyperalgesia. The mechanism of sensitization of central nociceptive neurons has been under active investigation in several laboratories. One contributing factor seems to be the release of EAAs in the dorsal horn, either from the synaptic terminals of nociceptors or from excitatory interneurons activated by nociceptive volleys. The EAAs act on both non-NMDA and NMDA forms of glutamate receptors. The NMDA receptors play an important role in the central summation of nociceptive events in the phenomenon known as wind-up, since NMDA receptor antagonists block wind-up (18,21). The activation of STT cells by noxious mechanical, thermal, and chemical stimuli is virtually eliminated by administration of the non-NMDA receptor antagonist, CNQX, into the dorsal horn through a microdialysis tube, but sensitization of the responses of STT cells by intradermal capsaicin injections is blocked by the NMDA receptor antagonist, AP7 (22). In addition, AP7 reduces the responses of STT cells to noxious mechanical, thermal, and chemical stimuli. Thus, the responses of STT cells to noxious stimuli depend on the activation of both non-NMDA and NMDA receptors, but sensitization of STT cells depends on NMDA receptors. In addition to EAAs, peptides appear to play an important role in central sensitization. This has now been investigated by introducing the NK1 antagonist, CP96,345, into the dorsal horn by microdialysis. This agent should prevent the effect of SP on NK1 receptors on dorsal horn neurons. The NK1 antagonist has an action very similar to that of AP7 in that it reduces the

responses to noxious stimuli and it prevents the sensitization of STT cells (91). The inactive isomer (CP96,344) is without effect.

ALTERATIONS DUE TO NERVE INJURY

Chronic pain can result from damage to nervous tissue. Neuropathic pain is now under intensive study using several recently introduced experimental models. The loose ligation model was developed by Bennett and Xie (5). In this model, four loose chromic gut ligatures are placed around the sciatic nerve of the rat. Within a few days, the animal begins to show guarding of the leg, and there is thermal and mechanical hyperalgesia (1,5). The hyperalgesia is present for at least several weeks, if not longer. One complication of this model is that there is progressive and severe loss of both myelinated and unmyelinated axons distal to the site of ligation, followed by regeneration (9). This complicates both sensory testing and the analysis of the responsible mechanisms. A role for NMDA receptors has been demonstrated in this model by Davar et al. (17). STT cells in neuropathic rats have an increased background activity, their responses to mechanical and thermal stimuli are followed by large after-discharges, and they have a relatively greater responsiveness to innocuous mechanical stimuli than do STT cells in normal rats (70). Another model that avoids some of these problems is the tight ligation model introduced by Seltzer and colleagues (77). One-third to one-half of the sciatic nerve is ligated completely, thereby causing degeneration of only one-third to one-half of the axons. The ligation effectively prevents regeneration, although there is presumably a neuroma at the site of ligation. The behavior of the animals resembles that of animals in the model of Bennett and Xie. More recently, Kim and Chung (38,39) proposed a different model. They ligate one or two spinal nerves tightly at a point just distal to the dorsal root ganglion. All of the peripheral axons belonging to the ligated spinal nerves degenerate. However, the number of axons and their peripheral distribution is under somewhat better control than in the Seltzer model, since this is a question of which spinal nerves are chosen rather than an estimate of how much of the sciatic nerve is ligated (although there is some variability in the degree of pre- or postfixation of the lumbosacral plexus from animal to animal). The animals develop mechanical and thermal hyperalgesia (38,39). The hyperalgesia is sympathetically maintained since it is eliminated by sympathectomy or by treatment with phentolamine (38). An important advantage of the Kim/Chung model over the Bennett/Xie model is that it can be produced in monkeys.

Changes in the Responses of Primate STT Cells in the Chung/Kim Model

The L7 spinal nerve was ligated tightly in several monkeys, with the result that the animals appeared to develop mechanical allodynia bilaterally. By the end of 2 weeks postoperatively, the mechanical allodynia was most pronounced on the side of the ligation. At this time, an acute electrophysiological study was done to determine if the responses of STT cells were altered (70). STT cells were recorded above and below the L6-L7 border, as well as on the contralateral side. It was found that the responses of STT cells in L6 to both mechanical and thermal stimuli were increased, both with respect to those of STT cells on the contralateral side in the same animals and to STT cells in previous experiments in the laboratory done on

animals without spinal nerve ligation. Of particular note were increased responses to innocuous and noxious mechanical stimuli, heating, and cooling.

SUMMARY AND CONCLUSIONS

1. Somatic pain is normally triggered by the activation of nociceptors. Particular types of nociceptors have been well characterized in cutaneous articular and muscle nerves. 2. The activation of cutaneous A nociceptors causes a sensation of pricking pain, whereas stimulation of C polymodal nociceptors elicits burning pain. Muscle nociceptors produce aching pain. 3. Unlike sensitive mechanoreceptors and thermoreceptors, nociceptors can be sensitized by damaging stimuli. Sensitization appears to be triggered by the release of chemical substances, such as prostaglandins, bradykinin, serotonin, and histamine, into the environment of peripheral nociceptor terminals. Some nociceptors are quite unresponsive until they are sensitized. 4. Nociceptors project to particular laminae in the spinal cord dorsal horn. Cutaneous A nociceptive fibers end in laminae I, II, and V, whereas cutaneous C polymodal nociceptors end chiefly in lamina II. Fiber, joint, and muscle afferents project to laminae I and V. 5. Fine afferent terminals, presumably of nociceptors, in the dorsal horn contain peptides, such as substance P and CGRP, and also excitatory amino acids. Both classes of substances are likely to be released during intense noxious stimulation. 6. Noxious stimuli trigger both excitatory and inhibitory events in the dorsal horn. Inhibition is likely to be mediated by such agents as inhibitory amino acids and inhibitory peptides. The circuits may be local or involve a supraspinal loop. 7. STT cells that project to the ventral posterior lateral thalamic nucleus in monkeys and rats have response properties that suit them for a role in the sensory-discriminative aspects of pain. Their input can be from cutaneous, articular, muscle and/or visceral receptors. Convergent inputs may account for pain referral. 8. The responses of STT cells are altered by pathological processes. These neurons become more responsive following damage of the skin by intense mechanical, thermal, or chemical stimuli. A similar change occurs during the development of experimental acute arthritis. It is proposed that sensitization of STT cells helps account for the development of primary and secondary hyperalgesia and allodynia following damage. 9. The mechanism of sensitization of STT cells is likely to involve excitatory amino acid and NK1 receptors. 10. Experimental models of painful neuropathy are being developed by several groups. The responses of STT cells in these models are altered in a fashion consistent with the development of spontaneous pain, allodynia, and hyperalgesia.

ACKNOWLEDGMENTS
The author thanks K. Gondesen and G. Gonzales for their technical assistance and Margie Watson for help with the manuscript. The work done in my laboratory was supported by NIH grants NS 09743 and NS 11255 and by an unrestricted grant from the Bristol-Myers Squibb Co.

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