Nociception

Nociception

Brain Research, 99 (1975) 229-245 229 © Elsevier Scientific Publishing Company, Amsterdam - Printed in The Netherlands Review Article NOCICEPTION ...

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Brain Research, 99 (1975) 229-245

229

© Elsevier Scientific Publishing Company, Amsterdam - Printed in The Netherlands

Review Article

NOCICEPTION

R. W. DYKES

Department of Physiology and Biophysics, Dalhousie University, Halifax, Nova Scotia, B3H 4H7 (Canada) (Accepted May 12th, 1975)

INTRODUCTION

The analgesias produced by acupuncture, electrical stimulation of the skin, and tactile stimulation can be attributed to the activation of large afferent fibres served by mechanoreceptors74,s4,100. Electrical stimulation of peripheral nerves15,16 or dorsal columns 77-79 at intensities sufficient to elicit mechanosensory illusions has been used to relieve pathologic pain. A satisfactory physiological explanation is needed to account for these results, to clarify the function of the spinothalamic system 65 and to provide a rational basis for clinical treatment of painful disorders 91. Until recently clinical observations of pathologic pain were discussed in the context of Head's epicritic and protopathic duality of spinal systems36, 7z despite its unsatisfactory explanation of the anatomy, physiology or psychophysics of any sensory modalitylL Recently the gate theory has gained popularity and has served as a theoretical framework for clinical observations56, 57. This theory hypothesizes that cells in the dorsal horn of the spinal cord act as a gate to the anterolateral pathway subserving pain. Cells of the substantia gelatinosa are said to be active, blocking information relay through the anterolateral system until small afferent fibres are activated by noxious stimuli. The gate theory states that the noxious input (i) directly activates anterolateral quadrant relay neurones, and (ii) inhibits cells of the substantia gelatinosa, releasing large and small afferent fibre terminals from presynaptic inhibition and thereby strengthening their influence on the anterolateral pathway; this double input is said to be necessary to evoke activity in the neurones of the pain pathway. But there is considerable disagreement about the evidence supporting this theory. Some workers have been unable to reproduce the positive dorsal root potential attributed to small fibres said to be the sign of presynaptic hyperpolarization 75. Further, the hypothesized suppression of A6 and C fibre activity attributed to activation of the larger myelinated

230 fibres does not occur 61,75. tn addition to its dubious veracity, the theory is incomplete: it cannot account for analgesias that outlast the duration of stimulation, such as those produced by acupuncture or electroanalgesiasT. Although now in question, the gate theory was the theoretical pivot of the current renewed interest in pain mechanisms, prompting extensive research H and serving as the rationale for clinical experiments to reduce chronic pathologic pain s6-ss. Data gained throughout the decade following its introduction have produced a need for a revised theory 75. The gate theory provides neurologists with no sound theoretical basis for the two most rapidly growing techniques for pain relief, i.e. acupuncture and electroanalgesia. Neurosurgeons can judge improvement in their treatment only by trial and error and, as one participant in a recent symposium on pain said, 'Our lack of understanding of the physiological and anatomical substrates of pain contributes to the often unsatisfactory long-term results...,~2. Meanwhile inadequate theory should not delay treatment of patients in pain. In one series, of more than 1500 patients with intractable pain 62~ obtained relief from transcutaneous electrical stimulation of peripheral nerves 78. Success has been reported with similar methods used to relieve acute pain after thoracic and abdominal surgery; Hymes e t al. 89 reported 80~ reduction in the subjective perception of pain in the majority of 115 patients. Electrodes implanted in the dorsal columns31 and thalamus zs in smaller numbers of patients also have been reported to relieve pain. CURRENT HYPOTHESES

(1) The gate control theory posits that activity in large myelinated fibres enhances presynaptic depolarization of axon terminals in the dorsal horn, inhibiting the passage of neural activity into the anterolateral system. More intense cutaneous stimuli are said to activate small fibres, causing presynaptic hyperpolarization of afferent fibres that activate nociceptive relay cells and simultaneously reduce the effect of the substantia gelatinosa cells thought to hold the gate closed. Metzack57 provides a recent statement of the theory and Mountcastle61 a recent critical summary. (2) Abrahams 1 suggested that prolonged changes in spinal cord responsiveness (and thereby in its relay capabilities) are due to descending effects on spinal interneurones, delivered via small afferent fibres from more central regions. Metzack and Melinkoff~s have proposed reticulospinal pathways that could mediate such influences. (3) Torebj6rk and Halling~,93 suggested, on the basis of data in humans, that the hyperalgesia produced by cutaneous electrical stimuli has little to do with mechanisms in the dorsal horn, but instead is due to conduction failure of small peripheral cutaneous nerve fibres. (4) Clark and Yang la and othersaS,5s attributed much of the analgesia of acupuncture to brain regions more central than the spinal cord. The analgesic effects of general anaesthetics, however, have been attributed to interference with neuronal transmission in lamina IV cells. Both sodium pentobarbita199 and halothane27 selectively reduce receptive field size and responsiveness of lamina IV neurones.

231 (5) On the basis of psychophysical data, Burgess 14 infers that small fibres block relay in large fibres - - not large in small as the gate theory suggests vS. (6) From behavioural and anatomical evidence provided by discrete lesions in monkey spinal cords, Denny-Brown et al. 2s argue that the input of both large and small fibres to the dorsal horn regulate relay through this region without requiring a gate mechanism or descending influences. (7) Crue z3 has reasserted the position of eighteenth-century psychologists 3~ that pain is 'an emotionally charged percept' and has emphasized the arguments o f pattern theory over those supporting the role of specific afferent fibres in the perception of pain 82. To evaluate these hypotheses in the light of recent experiments, the following sections summarize data on the afferent fibres entering the dorsal horn, its cellular constituents, the role of spinal pathways, and the putative relay cells of the spinothalamic tract. Conceptual problems with the dorsal column lemniscal (DCL) and anterolateral s vstems

There are severa! important challenges of the classical dichotomy which holds that fine touch, pressure, and position sense depend on activity in the DCL system and that crude touch, temperature, and pain result from activity in the anterolateral system a°l. For example, (1) in monkey, Perl and Whitlock 63 showed precise somatotopic organization of spinothalamic projection to the ventrobasal nuclei in the thalamus following dorsal column section, contrary to the theory that the anterolateral system conveys no somatotopic information. (2) Cook and Browder 22 showed that unilateral section of the dorsal columns in humans does not permanently alter twopoint discrimination, tactile location, or vibratory sense. (3) Semmes and Mishkin 76 found that monkeys with lesions of sensorimotor cortex ipsilateral to the tested hand show marked deficits in form and roughness discrimination. Since most dorsal column input is contralateral and anterolateral input is bilateral, this deficit appears due to loss of anterolateral input. (4) Behavioural testing of most assumed sensory functions of the DCL pathway shows their retention despite lesions of the dorsal columns. Thus, monkeys can detect and use vibratory stimuli as cues for discriminative behaviour and can use passive limb flexion in similar tests. The two-point threshold remains unchanged after transient postsurgical elevation. Similarly, dogs can use light tactile stimuli as a conditioned stimulus and cats can discriminate weight and the roughness of sandpaper. Even the tactile placing response is said to remain 62. Some of these results may be attributable to an alternative DCL-like route, the spinocervicothalamic tract, located in the dorsolateral quadrant of the spinal cord 5°. But this explanation is not tenable for the pain and temperature senses which can be evoked only by stimulation of the anterolateral quadrant and not the dorsal columns or dorsolateral quadrant. For example, one paradox of the non-lemniscal pathways is that information about locus and intensity of stimuli has never been found at their central terminations in the reticular formationS, 6 or the medial thalamus 66, yet precise information concerning locus and intensity is presented to these pathways by

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5sec Fig. 1. Discharges of a single C nociceptor during radiant heat stimulation of the skin. A: specimen records on various degrees of heating, Time course of skin surface temperature displayed below. B: relationship between the surface temperature of the skin and the total number of spikes/stimulus(Q) and the averaged number of spikes during the last 4 sec of any stimulus respectively (A). Regression line calculated from the points (O). Correlation coefficient 0.91. Stimuli of different intensities have been presented in randomized order with interstimulus intervals of 3 rain. The re~ptive field of this unit was in the plantar hairy skin of the second toe. Conduction velocity 0.63 m/see (Beck, Handwerker and Zimmermann, unpublished). Figure reproduced With permission of Zimmermann land Handwerker TM. the peripheral fibres at the level o f the dorsal horn, and psyehophysical data suggest that equally precise information is available centrally aS. Zimmermarm and Handwerker TM showed that C fibre nociceptors deliver to the dorsal horn graded neural responses about graded intensities of a noxious stimulus (Fig. 1). Psychophysical experiments demonstrated that precise, highly reproducible thresholds for pricking and burning pain exist and that both sensory dimensions are divisible into distinguishably different intensities a4. Adair et at. 2 have shown that pain sensations can be scaled by magnitude estimation techniques with a similar scale for different subjects. Darian-Smith and Dykes z5 demonstrated that man can judge precisely the presence and magnitude o f small thermal stimuli. A magnitude estimation technique demonstrated the availability o f at least 2.0 bits o f information about transient cooling of small skin surfaces. Studies of small myetinated afferent fibres in the median nerve of rhesus monkeys demonstrated neural responses in afferent 'cold' fibres sufficient to account for the psychophysical results obtained in man, assuming comparable peripheral neuronal apparatus. A more sophisticated experiment26, 47 demonstrated that the difference timen for cold pulses in man could be as small as 0.05 °C and that the responses o f at least 16 afferent 'cold' fibres must be considered simultaneously to obtain this precision in neural response to similar stimuli. Thus, afferent fibres convey precise information about both temperature and pain to the first synapse of the dorsal horn. Psychophysical data indicate that this information arrives at levels of consciousness, but it is still not known how this information is relayed centrally.

233 The classical concept that the anterolateral pathway relays little precise information centrally through the dorsal hornlZ,36,1°~ remains correct for some structures. There are large receptive fields with concomitant loss of somatotopic organization at the terminus of the spinothalamic tract in the posterior nuclei of the thalamus, and there is no evidence that those fibres ending in the ventrobasal complex convey any more precise information. Only the presence or absence of stimuli is distinguishable in neural records from the posterior thalamus 66 or from the trigeminal equivalent, nucleus caudalis z4, whereas cells served by the DCL path provide 6 or 7 categories of information about stimulus intensity, even at the cortex 6°. One suggestion consistent with such conflicting data about the precision of the anterolateral system is that it has a functional diversity not found in the DCL system. The anatomy, as well as the physiology noted above, supports this point: the anterolateral system consists of spinoreticular, spinotectal and spinothalamic components .5'5 which contribute to the reticular formation, tectum and thalamus. Clearly, our ideas of this system must be radically altered. The precision with which information is relayed in the anterolateral quadrant may not be the most relevant variable for understanding pain. In this region temporal aspects of anterolateral system activity appear most important: pain can continue, or remain suppressed, for extended periods following cessation of cutaneous stimulation - - a phenomenon we cannot at present explain. The evidence to be accounted for is clear: in disease states such as tic doloureux, light tactile stimuli may evoke prolonged paroxysmal pain, whereas short treatments with transcutaneous electrical stimulation can produce analgesias or hypalgesias lasting days or weeks after removal of the stimulus. These effects are not entirely psychosomatic ss and prolonged neural changes may occur near the periphery of the nervous system TM. AFFERENT FIBRES

There are two sets of peripheral fibres said to be nociceptive in function. They can be differentiated by size, conduction velocity, and response characteristics, and the dual quality of cutaneous pain appears to depend upon their differential sensitivity to noxious stimuli. Thus, certain fibres of Ad size evoke sensations of pricking pain, and certain C fibres evoke sensations of burning pain. Bishop and Landau t0, who electrically stimulated peripheral nerves at low intensities, elicited sensations of repetitive touch that remained unchanged, regardless of stimulus frequency, until the intensity increased 3-5 times. Then, pricking pain was reported followed by burning pain. In comparable physiological experiments in animals and man, A6 fibres were activated at intensities 3-5 times those required to activate the largest A fibres. When pressure was used to block conduction in peripheral nerves, both types of pain (together with warmth, cold, and some mechanoreception) were sensed as long as the Ad and C fibres continued to conduct, but only burning pain remained when the Ad fibres no longer conducted. The reverse sequence occurred when dilute anaesthetics were used to block peripheral nerves. Subjective reports following electrical stimulation of surgically exposed periph-

234 eral nervesZ0, 21 with different strengths indicated that various frequencies and patterns of activation of Aft fibres were invariably non-painful, whereas even a single stimulus at an intensity sufficient to activate the Ac~ fibres was painful. When the stimulus intensity was increased to activate C fibres, burning pain was reported when the stimulus exceeded 3/sec. Studies of single A6 fibres13, 64 serving both hairy and glabrous skin in cats and monkeys showed that the majority were low-threshold mechanoreceptive fibres associated with hairs and a few directly served the skin. However, at least 2 0 ~ of the Ab fibres required intense stimuli to be activated, and 10-14~o required mechanical stimuli clearly damaging to skin. Similar studies of C fibres s,42 showed that one-third were sensitive only to stimuli of greater magnitude than those activating other C fibres classed as mechano- or thermoreceptive afferent fibres. Thus, this group of C fibres was categorized as nociceptive in function. They differed from the A~ nociceptive fibres in being sensitive to noxious thermal, chemical, and mechanical stimuli. Thus, there are two subsets of small fibres activated by noxious stimuli. The characteristics of their responses support the proposition that afferent signals in one or both of these groups are necessary and sufficient to evoke painful sensations in conscious man. Only some small fibres are nociceptive, however, and the function of the other small low-threshold fibres poses another intriguing problem 9. Some of these are rapidly adapting mechanoreceptors activated by stimuli not consciously appreciated by man 59 and appear to have no role in perception. In monkey a third o f the A5 fibres may be thermoreceptive in function 25. THE ADEQUATE STIMULUS

If specific fibres respond selectively to noxious stimuli, it should be possible to define the characteristics of the stimuli that elicit this activity. Keele and Armstrong 49 suggested that the adequate stimulus is cellular injury sufficient to release chemical substances which activate terminals of nociceptive fibres. These substances probably are proteolytic enzymes that release algogenic polypeptides from gamma-globulins, which would support the idea that nociceptive afferent fibres are chemoreceptors 17,51. With this idea in mind, Besson et al. 7 successfully used intra-arterial injections of bradykinin to deliver a specific nociceptive input to the dorsal horn. Response characteristics of small fibres The serious technical problem of recording from small myelinated fibres hampered attempts to learn about their response characteristics. Adrian a and Zotterman 105 first discussed the possible nociceptive function o f small fibres, but it was not until the studies of Perl and his co-workers that recording techniques were developed for assaying large numbers of small fibres. Burgess and PerP a sampled 513 A6 fibres from cat skin and demonstrated that the majority (78 ~) were responsive to small hair movements or other innocuous stimuli. However, 14 ~o of the sample responded only to mechanical stimuli visibly damaging to the skin; these fibres could be classified as nociceptive (21 ~ of the sample had very high thresholds but only 14 ~ required visible

235 damage for activation). Those termed nociceptive had punctate receptive fields, each consisting of 5-20 spots, distributed over a 1 cm × 2 cm oval area of skin. Conduction velocities ranged from 6 to 36 m/sec (mean =: 19.5 m/sec). Per164 described fibres, from glabrous and hairy skin of squirrel monkeys, with similar response properties. Of 378 fibres, 20 ~,,iwerenociceptive; 12 ~ required stimuli that visibly damaged the skin. This latter group had punctate receptive fields and their conduction velocities were between 5 and 28 m/sec (mean -- 23 m/sec). Iggo 43 reported one myelinated fibre with similar properties from another primate; as in the cat, the majority of A6 fibres responded to innocuous stimuli. In rhesus monkeys, a third of the fibres may be thermoreceptive25, 3° and the rest respond to innocuous mechanical stimuli to hair or skin 64. In 1959 Iggo presented data on a small number of C fibres that responded to noxious mechanical and thermal stimuli 41. With improved recording techniques, Bessou and Perl s studied 147 C fibres. As the Ab fibres, many (36~) of the C fibres responded to innocuous tactile stimuli or moderate warmth and cold; 16 ~ responded to firm, non-painful pressure; and about 30 ~, polymodal nociceptors 8, were excited by noxious heat stimuli, irritant chemicals and damaging mechanical stimuli. Recently, Zimmermann and Handwerker TM demonstrated that with adequate stimulus control one can quantify the relationship between damaging skin temperatures and the discharge frequency of a polymodal C fibre nociceptor. Three conclusions can be drawn from these experiments in cats and monkeys. (1) High-threshold afferent fibres are not equiwdent to small afferent fibres; the majority of both A5 and C fibres respond to innocuous stimuli. (2) A subgroup of A5 fibres ( ~ 1 5 ~ ) is clearly nociceptive in function. This subgroup's characteristics parallel the psychophysics of pain, having punctate receptive fields for mechanical stimuli, rapid adaptation to steady stimuli, and a relative insensitivity to heat and chemicals. Similarly, the responses of nociceptive C fibres to some algogenic stimuli parallel the sensations attributed to burning pain 65. Like the pain produced by heat and chemicals the neural response of polymodal C fibres to these stimuli is slow in onset and does not adapt. (3) The dichotomy between pricking and burning pain and their respective associations with A6 and C fibres emphasized by Bishop and Landau TM has been upheld by the differences in function observed in single A6 and C nociceptive fibres. Burgess 14 has summarized the types of primary afferent fibres in peripheral nerves of mammals and has assigned putative sensory functions to activity arising from each category (Table I). THE DORSAL HORN

Despite the controversies surrounding the function of this area, 3 statements can be made unequivocally61. (1) The AO and C fibres provide the dorsal horn with a major excitatory input that produces postsynaptic activity in the anterolateral quadrant. This activity is not reduced by electrical stimuli that activate cutaneous Aft fibres 53,54. At least 15 ~ of

236 TABLE I THE PATTERNS OF ACTIVITY PRODUCED BY VARIOUS CUTANEOUS STIMULI ARE SHOWN TOGETHER WITH THE SENSATIONS THEY PRODUCE

The number of plusses indicate relative increase in frequency, negative symbols indicate inhibition, and zeros no known effect. Table reproduced with permission of Burgess14. Fiber size

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* Touch is a complex experience that includes simple contact, vibration and texture sensations, and tickle, depending on which meehanoreeeptors are active. ** Cold receptors have been found to respond when the skin temperature exceeds 43-44 C and some response may persist at 50 °C. Apparently not all cold receptors have this paradoxical response. *** A weak and inconsistent response is obtained from some position-sensitive meehanoreceptors during stimulation with acid that damages the skin. this i n p u t is d e p e n d e n t u p o n noxious s t i m u l a t i o n o f c u t a n e o u s structures °5 via axons t h a t do n o t send collaterals to the dorsal c o l u m n nuclei. (2) Full surgical section o f the dorsal h o r n ' s o u t p u t , the anterolateral q u a d r a n t , provides hemi-analgesia in m a n , b e g i n n i n g a few segments below the level o f transection 1°2, whereas section o f the dorsal c o l u m n s alone does n o t lead to loss o f p a i n sensibility. Thus, structures in the dorsal h o r n a n d the two sets o f nociceptive afferent fibres are necessary for painful sensations. (3) Further, the A 6 a n d C fibres enter the spinal cord over the more lateral divisions o f each dorsal root, a n d destruction o f this lateral division results in analgesia4o, 68,69, loss o f nociceptive reflexes, and loss o f evoked potentials in the anterolateral system sz. It follows that the large myelinated fibres do n o t activate the anterolateral p a t h w a y directly, (though they m a y modify the effect o f small-fibre i n p u t t o the pain p a t h w a y a n d thereby exert a n indirect influence).

237 Rexed 71 divided the dorsal horn into 6 layers according to neuronal size, distribution and orientation. The majority of the cells in all layers receive terminals from A6 and C fibres; frequently both converge on a single cell 1s,37,9°,97. The large marginal neurones of lamina I, the most dorsal layer, are activated from both cutaneous A~ and C fibres and are sensitive to both noxious and thermal stimuli TM. Unequivocal recordings have never been obtained from the small cells of laminae lI and III. Some cells of these layers have been activated antidromically from the brain stern and may be relay neurones of the spinothalamic tract29, sg. However, the cells of origin of spinothalamic fibres are located uniformly throughout nearly all regions of the spinal grey matter4, 94-96 and thus are not preferentially found here. The cells of lamina IV respond to light mechanical stimulation within small receptive fields 97,98. Their response characteristics suggest that fibre collaterals in the dorsal columns may activate them. Cells of the subjacent layer (V) have receptive fields with excitatory centres and inhibitory surrounds whose characteristics suggest that these neurones receive convergent input from a number of cells in lamina IV '~v. Lamina VI is organized independently of the first 5 layers; its neurones are activated by gentle movements of the limbs, thus appearing to receive input from muscles and joints. The substantia gelatinosa (laminae II and III) is an unusual structure. Apparently it is a closed system: some axons of its cells remain within laminae II and III or return to them after short longitudinal courses, and some cross to the substantia gelatinosa of the other side via the interconnection in the posterior white commissure. The system contains an unusually large number of axo-axonic synapses; the small afferent fibres from the lateral division of the dorsal root end in laminae II and Ill primarily on dendrites of cells of lamina IV which project into the substantia gelatinosa, but they also end as axo-dendritic synapses on other substantia gelatinosa cells. Other axo-dendritic synapses found in the substantia gelatinosa are those of the substantia gelatinosa cells themselves, synapsing en passant upon one another 67,7°. The output of the substantia gelatinosa is unknown; all identified axons leaving it travel only short distances in Lissauer's tract or the fasciculus proprius and then reenter the substantia gelatinosa. The large cells of layer IV appear ideally suited as efferent cells, since their dendrites pass at right angles to, and make contact with, most of the gelatinosa axons and receive direct contact from both large and small afferent fibre terminals. However, their axons disappear in the fasciculus proprius ~9. The recent experiments of Trevino et al. 96, showing almost uniform distribution of spinothalamic neurones from all layers of the horn, make the functional relations between the dorsal horn and the anterolateral pathway even more enigmatic. The fact remains that the substantia gelatinosa is strategically located to exert a controlling influence on the anterolateral pathway. However, there is insufficient knowledge of the synaptic connections, afferent supply and functional organization of this region to clarify its role in the regulation of the sensory experience of pain. EXPERIMENTS RELEVANT TO CONTROL MECHANISMS OF THE SUBSTANTIA GELATINOSA

Volleys of impulses evoked by electrical stimuli to peripheral nerves arrive in the

238 dorsal horn along afferent fibres and produce prolonged depolarization of primary afferent terminals. This event can be recorded outside the cord as a potential change known as primary afferent depolarization (PAD)56, 75. PAD is accompanied by depression of the segmental reflex and by depolarization of primary afferent terminals in adjacent and contra[ateral spinal roots 46. Fibres of one modality tend to influence fibres of the same modality, thereby enhancing differences between the active centre and the surrounding regions. The effect appears to be typical presynaptic inhibition functioning as negative feedback at the first synapse45, 75. Through this mechanism the substantia gelatinosa may control the excitability of primary afferent terminals, thereby regulating the synaptic relay of afferent activity. Melzack and Walt 56 suggested this regulatory role for the substantia gelatinosa to account for the observations that activity in large myetinated fibres suppresses pain arising from the region innervated by them, and that spontaneous pain may arise in such a region if it is denervated of its large-fibre innervation 102. One step in clarifying the interpretation of the PAD is to assess the contribution of the various categories of afferent fibres ending in the dorsal horn. Less than 20 o/~ of the input to the horn arises from nociceptive afferent fibres; the majority is from mechanoreceptive fibres activated by light stimuli to hair or skin. Whatever the function of the dorsal horn, it is not limited to modulation of nociceptive information. This is apparent from the work of Denny-Brown et al. 2s, who recently repeated some of Sherrington's experiments. Sherrington s0,sl defined a dermatome by isolating the nervous supply to a skin region; exposing 7 dorsal roots he sectioned three on each side of the one to be studied. Denny-Brown et al. 2s repeated this in rhesus monkeys and mapped the zone of remaining sensation. The area of the resulting dermatome is highly reproducible; its border remains stable (-~ l-2 ram) for many months. However, if two additional roots are cut, one on each side of the isolated root, the dermatome area increases to a new stable size. Thus, the size of the isolated dermatome from which reflexes can be elicited is determined not entirely anatomically, but is due in part to a prolonged, stable, functional input from adjacent portions of the spinal cord. With additional lesions of the cord or spinal roots, Denny-Brown et al. zs have shown that each point on the skin is represented in at least 5 spinal roots, that a tonic input from one spinal root is conveyed up and down the cord in Lissauer's tract for 5 or more segments, that an excitatory component travels in the medial portion of Lissauer's tract and an inhibitory one in the lateral portion, and that both large and small fibres contribute to both the excitatory and inhibitory parts of Lissauer's tract. Thus, they have elucidated a mechanism (without a gating function) to regulate relay o f all sensory information through the dorsal horn. The proposal has a strong anatomic basis s9 and is consistent with the data described below. Gray 33 has considered the dorsal horn as a synaptic region where a barrage of impulses arrives and undergoes transformation in time and space, the resulting modified array being relayed to the next stage. Fuller and Gray 32 applied this approach to input from low-threshold rapidly adapting mechanoreceptors and provided an example of how the dorsal horn might process tactile information both spatially and

239 temporally. By delivering small, discrete tactile stimuli to the pad of a cat's forelimb while recording from cells in the dorsal horn, they demonstrated that the tactile stimuli interacted in the dorsal horn so that the second of two stimuli activated dorsal horn cells optimally only if it occurred at about 5 mm from the first and with a delay of 10-15 msec. Stimuli either earlier or later, or physically closer to the first stimulus, produced smaller responses. J~inig et al.44, 45 demonstrated modality-specific information processing in the dorsal horn. By delivering distinctive mechanical stimuli to the cat's footpad and recording from afferent fibres, they could actiwtte graded fractions of a population of about 53 afferent fibres from Pacinian corpuscles or 60 afferent fibres from slowly adapting receptors 44. These graded, modality-specific afferent barrages were evoked while recording from cells in the dorsal horn, to demonstrate that the PAD generated by a homogeneous afferent population reflects feedback inhibition of the classical surround type directed specifically towards afferent terminals from receptors with functional characteristics similar to those producing the PAD. A PAD produced by afferent fibres from Pacinian corpuscles was rapidly adapting and primarily affected afferent fibres from Pacinian corpuscles and rapidly adapting fibres associated with hair, whereas a PAD generated by slowly adapting fibres reflected presynaptic inhibition of slowly adapting fibres. The effect of the rapidly adapting fibre PAD on the slowly adapting fibres was minute compared with the modality-specific effect. Tapper et al. 9° identified 4 types of afferent fibres and determined their patterns of convergence upon dorsal horn cells. Although specifying neither that the inputs were monosynaptic nor that the second-order neurones were spinothalamic cells, they showed that the patterns of connectivity to the dorsal horn neurones in their sample were independent of one another. Further, the relative abundance of the inputs paralleled the frequencies of their fibres in the peripheral nerve. In some of the cells, modality specificity was maintained, as well as a localized receptive field. For these neurones, the convergence ratios were 60 fibres per cell for one type of slowly adapting fibre, and 53 and 74 fibres per cell for a large myelinated and a small myelinated rapidly adapting fibre, respectively. The discrepancies between these data and others (e.g., Wagman and Price 97 reported no modality specificity) remain to be explained. In 52 cats, Christensen and Perl is have identified l l 0 cells in lamina 1 of the dorsal horn which were selectively activated by noxious or thermal stimuli. The cells were identified as those responding to A6 and C fibre volleys. They had punctate receptive fields and fell into 3 categories: (1) those responding to noxious mechanical stimuli and having only the A6 fibre input, (2) those responding to noxious lnechanical, thermal, and chemical stimuli and having both C fibre and A6 fibre inputs, and (3) those responding to innocuous thermal and noxious mechanical stimuli. Since the preceding experiments have not identified their samples of dorsal horn neurones as relay neurones, one might argue that these data represent a mixture of interneurones, and members of short spinal pathways, as well as actual spinothalamic tract neurones. Only a few recent experiments have involved known spinothalamic tract cells. Willis eta/. t°3 and Trevino eta/. 94-96 identified populations of spinothalamic tract neurones by antidromic activation of axons located in the spinothalamic

240 region of the thalamus. The results indicated that several components to the spinothalamic tract can be identified by: (1) location of the cell bodies, (2) conduction velocities of the axons, and (3) response characteristics. Further, the relay neurones were somatotopicalty organized. Surprisingly only 15 ~ showed inhibitory receptive fields, and, when present, the inhibitory area was often contralateral. An unexpected negative finding, possibly due to the anaesthetic, was the absence of neurones having only a thermoreceptive input. Another interesting observation was the presence of many spinothalamic tract neurones with low thresholds; of 138 cells, 38 % were activated by deflection of single hairs, 21% by forces of I g or less, often by forces of less than 100 mg, The spinothalamic tract is more complex than is generally recognized. RECAPITULATION

The neurophysiological basis of pain is poorly understood. Several relevant mechanisms have been enumerated. Although more information is needed for adequate evaluation, it appears reasonable to postulate the existence of cells which respond only to nociceptive input and relay this information centrally. It is also clear that in the dorsal horn the arriving cutaneous input is subjected to important modifications which cannot be attributed simply to an effect of large fibres upon small ones, since these changes are organized by receptor type and by peripheral topology. This arrangement leads to interactions within specific receptor populations, with a predominance of central excitatory and surrounding inhibitory effects. Lissauer's tract plays a prominent role in relaying these excitatory and inhibitory effects to adjacent spinal regions thereby providing a strong (and probably modulating) second input to the substantia gelatinosa at those more distant points. The system's complexity and organization by specific receptor categories require that it be analyzed with appropriate natural stimuli during experiments on single units. The experiments of Denny-Brown 2s suggest that spinothalamic cells may be influenced strongly by a combination of excitatory and inhibitory inputs from skin regions outside the actual receptive field, but Willis and his colleagues95,1°3 found the classic inhibitory surround only in a minority of cells, and J~inig et aL 44,45 show feedback influences only during the presence of an afferent barrage, implying that the influences postulated by Denny-Brown et al. 2s are not demonstrable as the classic centre-surround receptive field. Such tonic excitatory and inhibitory effects may have other roles in the dorsal horn. Wall 9s,99 observed a restriction of receptive field size following stimulation of descending pathways. If such effects are organized at the spinal level, they may decrease or increase the efficacy of stimulus increments (the experiments of Rowe and Carmody 73 provide a model) or act as a 'subliminal fringe' enhancing or decreasing spatial or temporal summation. The first role would produce changes of slope in the stimulus-response relationship of the second order cells. The second role could allow subthreshold stimuli to activate neurones when the surface area of the stimulus was increased or when stimulus frequency increased. The insight into dorsal horn organization provided by recent data should lead to

241 n e w e x p e r i m e n t s o n t h e f u n c t i o n a l c h a r a c t e r i s t i c s o f this r e g i o n w i t h results t h a t can account for the puzzles of acupuncture and electroanalgesia.

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