Somatosensory receptors and their CNS connections.

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Annu. Rev. Physiol. 1975.37:105-127. Downloaded from www.annualreviews.org Access provided by Technische Universiteit Eindhoven on 01/23/15. For personal use only.

SOMATOSENSORY RECEPTORS

+1125

AND THEIR CNS CONNECTIONS Bruce Lynn Department of Physiology. University College London. London. WC I. England

INTRODUCTION This review deals with recent findings concerning the properties of receptor units in the somatosensory system and the connections of their afferents in the central nervous system. Frequent references are made to articles in the recently published Volume II of the Handbook of Sensory Physiology (72). I have divided this review into four main sections, corresponding roughly to the subdivisions of kinesthesis, touch and pressure, warm and cold, and pain.

LIMB MOVEMENT AND POSITION Three main groups of receptors send information to the central nervous system about the position of the limb and about changes in its position. These are the stretch receptors in skeletal muscles· and tendons, the mechanoreceptors in the joints, and certain of the skin mechanoreceptors. Cutaneous mechanoreceptors, which appear to play only a small part in kinesthesis (34) and are not usually considered as proprioceptors, are dealt with in the next section. However, it is worth noting that many hair receptors must fire during limb movements and that slowly adapting Type II receptors are excited by joint movements and must be capable of transmit ting information about both movements and the fixed position of a limb (30, 84).

Afferent Inflow from Joints The discharge characteristics of single afferent fibers from joint receptors have been reviewed recently by Matthews (t03) and Skoglund (145). A number of recent studies have emphasized the relative lack of activity from slowly adapting afferents when the joint is held near its midposition, compared with activity near the limits of movement. Out of 278 single myelinated fibers running from the knee joint of the cat, only 4 fired best when the joint was held at an intermediate position. while 199 fired best when the limb was held at extreme flexion, extension, or both (23). These results, particularly the finding of many units activated at both extreme flexion and 105


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extension, are quite dissimilar from previous studies; some possible reasons for the differences are considered by Skoglund (145). One fact pointed out by Burgess & Clark (23) is that. for technical reaSOns, earlier studies of knee joint afferents did not systematically test units at full flexion and full extension. All slowly adapting afferents from the intercostal-vertebral joints of cats and rabbits were found to respond best at one of the·extreme joint positions but never at both (50). Most units (72% of 48) fired with movements in the expiratory direction, while 28% fired best with inspiratory ·movements. However, units were active over most of the range of normal movement of these joints. and responded in a cyclical manner during sponta neous respiration. Recordings from the elbow joint nerve of the cat showed that greatest activity occurred at full extension, with much less activity at the midposi tion or at fuJI flexion (107, 108). The dynamic responses of slowly adapting receptor units from the eat's knee have been examined using small, low frequency, sinusoidal displacements (I05). Re sponses have been related to the static sensitivity functions, which were usually monotonic over the limited range of movements studied. Changes in phase and gain with frequency were found to fit a "fractional-order differentiator" model (lOS). A substantial minority of joint afferents are rapidly adapting: 10% from the intercostal-vertebral joints (50) and 16% from the knee joint (23). At the knee joint these were subdivided into two categories by Burgess & Clark (23); I. Padnian corpuscle-like units that fired to distant taps and 2. generally less rapidly adapting units that did not respond to distant taps but could often be fired tonically by combined extension and outward rotation of the lower limb. Joint afferents from the eat's elbow were found to respond to muscle contraction . even in the absence of joint movement. They also respond to 100Hz vibration applied to muscles inserting and originating at the elbow (l08). A small number of muscle spindle afferents were found to run in the posterior articular nerve from the eat's knee (23).

Central Connections o[ Joint Afferents Cells activated by slowly adapting joint afferents have been reported by a number of workers in the dorsal column nuclei (DCN), and it had appeared that such units were 'activated �ia primary afferent collaterals in the dorsal columns (145). For the forelimbs such an' arrangement has been confirmed by recent studies. The funiculus cuneatus contains many fibers responding with a slowly adapting discharge follow ing forelimb joint rotation in the squirrel monkey (166). Also. cortical evoked potentials following electrical stimulation of the elbow joint nerve of the cat are largely abolished'by dorsal column section (33). However, a quite different situation is found for the hind limb. No slowly adapting joint afferents are present in the cervical funiculus gracilis of either cat (15, 24, 32) or monkey (166). Many of the rapidly adaptingjointafferents from the hindlimb, particularly those from Pacinian corpuscle-like receptors. do contribute axons to the cervical dorsal columns of the cat (24, 32). Joint afferents from the forelimb weakly excite some of the postsynaptiC fibers in the dorsal columns. Uddenberg (154) and Skoglund (145) suggested that such fibers


SOMATOSENSORY SYSTEM

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may carry the information from slowly adapting (SA) hindlimb receptors. However, no such units have been reported in samples of cervical dorsal column units (166), even those which concentrated on postsynaptic units (122). A recent study of cells in the gracile nucleus that are excited from the cat's knee joint failed to find any SA units, but found 59 units that responded with a rapidly adapting discharge following limb movement (168). Williams et al (168) suggested that previous studies of joint units in the DCN may also have been looking at this same population since criteria for classifying units into slowly adapting (SA) and rapidly adapting (RA) were not comparable with those used in studies of primary afferents. This may be the case for some joint units in the DCN, but it is not true for claw units that respond with a high frequency discharge for many seconds when the terminal phalangeal joint is held at a suitable, fixed angle (54). It may be significant that slowly adapting discharges following hindlimb claw displacement were observed in the thoracic dorsal columns (24). In agreement with the unit studies, it has been found that cortical evoked poten tials following electrical stimulation of the axons of the SAjoint afferents are usually not reduced by dorsal column section (33), although those from RA afferents are substantially diminished. However, section of the dorsolateral funiculus (DLF) ipsilateral to the stimulus (contralateral to the cortical recording site) did substan tially reduce potentials from SA afferent stimulation (33). A number of ascending systems run in the dorsolateral funiculus, including the spinocervical tract (SCT) and the dorsal spinocerebellar tract (DSCT). Kowever, the DLF was sectioned at Cl, above the lateral cervical nucleus, in the experiments of Clark et al (33). Also, no cells giving a discharge related to limb position have been found in the SCT or the lateral cervical nucleus (119). Thus the SCT does not appear to be involved in detecting limb position. The DSCT, or a parallel system of relay neurones from the Clarke's column area, appear to be much more likely candidates. Clark (32) showed that SA joint afferents did run in the cat dorsal columns, but only as far as L3·Th13 segments in most instances. In agreement with this, cells in Clarke's column that receive a monosy naptic input from the SA joint afferents have recently been described (87, 96, 97). Such cells often responded only to one direction of movement in two joints and some also received cutaneous andlor muscle inputs (87). Many units only fired over the last 15-200 of a joint movement (97) like many of the primary afferents (23). Joint cells in Clarke's column resembled muscle cells in having a relatively regular dis charge pattern and rather large excitatory post-synaptic potentials (EPSPs) (88). It therefore appears probable (33) that the information from SA joint afferents projects via a similar path to that from muscle stretch receptors (92). Muscle Stretch Receptors

Three types of stretch receptors are found in mammalian muscle: the Golgi tendon organs and the primary and secondary endings of spindles. The afferent discharges from these endings have been studied for two generations ( l 02, 103). An extensive account of the properties of mammalian muscle receptors has recently been pub lished (103) and they will not be considered further here. The synaptic effects of the


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different types of muscle afferents on neurones that project to the cerebellum have also been examined in detail ( l l8). The classical view that muscle, as well as joint, receptors play a part in producing sensations of limb movement and position (kinesthesis) has recently been revived by experiments using tendon vibration as a means of specifically exciting muscle spindle primary endings (51 ). However, vibration also excites two other types of receptors: those in adjacent joints (l08) and Pacinian corpuscles throughout the limb (69). Goodwin et al (51) also claimed that, in contradiction to previous studies ( 1 06), complete finger anesthesia does not cause movements of the fingers to pass un detected. Direct stretching of the tendons of the forearm muscles that cause finger flexion has also recently been found to give rise to sensations of finger movement (104), another result that conflicts with an earlier study (49). The lack of any serious loss in sense of limb position following total hip replacement would also appear to indicate that the muscle receptors play an important role (51). Since the majority of SA joint alferents may only fire within 10-20° of extreme flexion or extension (23) it would be interesting to have the sense of limb position tested for extremes of movement in patients with surgical joint replacements. Central Connections

0/ Muscle Stretch

Receptors

The cortical projection pathways from muscle stretch receptors now clearly take on a more "normal" appearance, si�ce it had appeared that this projection might represent a cortical receptor pathway with no parallel in conscious sensation ( 103). Recent work on the central pathways carrying information from forelimb muscle receptors has been reviewed by Rosen (134). The connections of afferents of Golgi tendon organs and primary spindle endings have so far received most attention. Cells in the main cuneate nucleus that send axons in the contralateral medial lemniscus are excited only by primary ending afferents and not by tendon organ afferents (135). 72% of such cells were fired from only I of 4 wrist extensor muscles tested, and 21 cells tested from both wrist flexors and extensors were never excited by both (136). In the specificity of their afferent connections, these cells resemble those in both the external cuneate nucleus and Clarke's column that project to the cerebellum ( 1 35, 136). The muscle afferents that terminate in the cuneate nucleus appear to run via the cervical fasciculus cuneatus (135, 166). The pathways for muscle afferent information from the hindlimb are more com plex. Afferent fiber collaterals run for a short distance in the lumbar dorsal columns and terminate on cells in Clarke's column. These cells in tum send axons to nucleus Z in the medulla ( 1 3, 92). The pattern of highly specific connections displayed by cells in Clarke's column is repeated in nucleus Z. For example, 2 1 cells were excited by group I volleys from only one out of the three muscle nerves tested (92). Some cells were also fired by cutaneous (sural) nerve stimulation. The similarities of the projection patterns and properties of the relay from hindlimb muscle afferents to nucleus Z and to the cerebellum raises the possibility that axons in the DSCT divide to terminate in both regions. It also seems likely that hindlimb joint afferent infor mation follows a similar route (33).



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A group of cells in medial lamina 6 of the upper cervical cord receives an excitatory monosynaptic input from muscle stretch receptors in the lower limb ( 133). These cells also receive an excitatory cutaneous input (133). A number of reports of cells in the lumbosacral cord that respond to limb movements have appeared (157, 159, 160, 169). Such cells are found in the most ventral part of the dorsal horn (lamina 6) and in the intermediate and ventral gray matter. Some of these cells send axons to the contralateral thalamus (169), while others project in the ipsilateral DLF (4). These latter cells were found in the medial parts of laminae 5, 6, and 7 in segments L5-6 and were monosynaptically excited from a number of muscle nerves, and also sometimes from joint and skin nerves (4).

NON-NOXIOUS MECHANICAL EVENTS ON THE SKIN

Properties of Afferent Mechanoreceptor Fibers Studies in the 1960s established the basic properties of cutaneous mechanoreceptor afferents in mammalian hairy skin and subdivided these into a number of categories according to the caliber of their axons (and whether myelinated or unmyelinated), the nature of any macroscopic structures associated with their terminations (e.g. hairs), their rate of adaptation to a constant displacement, the form of their receptive fields, and other factors (10, 18, 28). Because much of this work has recently been reviewed in depth by Burgess & Perl (27), I will concentrate on work that has appeared subsequently. The encapsulated Rllffini corpuscle has been identified as the receptor ending for Type II slowly adapting afferents in cat hairy skin (30), and its fine structu.e has been examined using the electron microscope (3, 30). Further details of the re sponses of Type II endings to controlled skin indentation and to skin stretch are also given in this study, including quantitative data on input-output relations and on rates of adaptation. Disagreements continue about the classification of hair afferents with large myeli nated axons. The T (for tylotrich hair) and G (for guard hair) classification devel oped by Brown & Iggo (18) appears to correlate well with regional differences in the fur of rabbits (17). Burgess and associates (25, 27, 28), however, continue to treat all large hairs as alike, calling them guard (G) hairs, and prefer to classify afferents according to their velocity thresholds. The original subdivision into G) (high velocity threshold) and G2 (low velocity threshold) (28) has been extended to include an intermediate category called "intermediate hair" (27). For the sural nerve, this category has been found to include many units previously classified as Pacinian corpuscles (25). There are, however, a very small number of genuine Pacinian corpuscles with axons in the sural nerve (69), but they comprise much less than the 4% of myelinated afferents claimed previously (28). A further hair unit classification has been used by Tapper et al (148). These workers subdivided the afferents from the larger hairs into G (low velocity thresh old) and G' (stiffest hairs, high velocity threshold), and suggested that their G class included the G2 and intermediate classes of Burgess & Perl (27) and their G' class the G) (27) and T (18) classes.

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The continued failure of different laboratories to agree on one classification scheme produces a certain skepticism towards all the published schemes. However, the demonstration that central cells may be excited by only one category of hair afferent (20, 110, 148) suggests that important functional differences may be in


volved.

A recent study in monkeys (167) examined the responses of myelinated hair afferents on proximal leg skin to tangential brushing along straight lines across the receptive fields. No differences were reported between different types of hairs. The patterns' of response did not depend upon the direction of brushing, although directional properties were observed for some cortical neurones studied using the same stimuli (167). Tapper et al (148) have provided some useful data on the innervation density of hair receptors in cat skin. They have counted the myelinated fibers in the posterior femoral cutaneous nerve and the numbers of down and guard (including tylotrich?) hairs per unit skin area, and have determined the numbers of hairs innervated by single afferent fibers and the areas over which these were spread. From such data they have been able to make estimates of the minimal numbers of fibers of each type innervating unit skin areas. They found at least 2.5 G units and 2.9 D (down hair) units for each cm2. A simil3,r analysis was presented for Type I slowly adapting units (innervating touch �orpuscles), and once again a minimum figure of approximately 2.5 units/cm2 was found. Complete maps of all the touch corpuscles on the posterior femoral skin have been published by Burgess et al (29) in connection with a study of the factors determining the pattern of regeneration following nerve injury. Bur gess et al (29)- noted that touch corpuscles are almost never found within I mm of each other in normal skin, a situation that. would not occur if they were distributed at random. The. large sinus hairs of the face and wrist continue to receive attention. The slowly adapting terminations on the sinus hairs have been subdivided into two categories corresponding to the· Type I and II categories for SA. receptors .in hairy skin (55). Two types of rapidly adapting endings, one with a high velocity threshold and Pacinian corpuscle-like behavior and one with a lower veiocity threshold, have been found associated with the facial sinus hairs (including the true vibrissae) (55). From microdissection experiments and comparison with the anatomical data of Andres (2) and Nillson (115), the following structure-f�m�tion correlations are propqsed (55): Type I SA Merkel cell-neurite complexes in the outer root sheath; Type II SA lanceolate nerve terminals outside the glassy membrane surrounding the outer root sheath; Pacinian corpuscle-like units lamellated Golgi-Mazzoni corpuscles. No structure could be assigned with any certainty to the relatively uncommon, low velocity RA units. These correlations fit well with other studies. For example, Sakada (140) found that the rapidly adapting, vibration-sensitive receptors in th e periostea of the eat's jaw were also Golgi-Mazzoni corpuscles. Also Merkel cell-neurite complexes are known to be SA receptors in touch corpuscles (Type I receptors) from mammalian hairy skin (70, 73). Merk el cell:-neurite complexes have also been found at the locations of SA receptors in cat (76) and raccoon (lll) glabrous skin. High velocity =

=

=



III

threshold units are not found in the carpal sinus hairs (55, 115), nor are Golgi Mazzoni corpuscles (115). The many Pacinian corpuscles situated close to the carpal hairs (116) presumably perform the same function (55). The receptor categories recognized by Gottschaldt el al (55) in cat vibrissae bear a close resemblance to the four categories defined by Zucker & Welker (170) in the rat. It is more difficult, however, to relate to these categories the data from studies using sinusoidal vibration of cat whiskers (57, 113, 114). A detailed study of the responses of rapidly adapting afferent units with intracu taneous receptors (i.e. not from Pacinian corpuscles) in monkey glabrous skin has been made by Johnson (77). The thresholds for different patterns of activation by a 40 Hz sinusoidal displacement have been determined for different positions in receptive fields. Changes in threshold appear to follow a simple pattern, apparently determined largely by mechanical factors. From the distribution of thresholds over the population as a whole and the form of recept ive fields, Johnson (77) has com puted the population input-output relations for his particular stimulus using a computer model. Total impulse firing over the whole population is calculated to rise linearly with stimulus intensity, despite the nonlinear relation for individual units. These findings, and the general approach, have much in commOn with the more extensive studies by Gray and his colleagues (5, 6, 48, 56, 99) of rapidly adapting mechanoreceptor units from the glabrous skin of the cat's plantar cushion (large foot pad). These earlier workers were able to check the validity of their model of the system by measuring the summed activity from the pad nerves (6, 48). It would clearly be useful if some similar recordings could be made from the monkey prepara tion of Johnson (77). Four types of mechanoreceptor with large myelinated axons have been distin guished by Pubols & Pubols (131) in a study of afferent fibers from the glabrous skin of the raccoon forepaw. The four categories are Pacinian corpuscles, rapidly adapt ing, moderately slowly adapting (MSA), and very slowly adapting (YSA). This classification supersedes an earlier one of just RA and SA (130). Recent studies of afferent C-fibers from human skin (151, 155a) have failed to find any sensitive "C-mechanoreceptors" similar to those reported in cat hairy skin (10). Torebjork & Hallin (l51) studied nerves (including saphenous) that innervate both hairy and glabrous skin of the hand and foot. This situation contrasts with the abundance of such units in cat hairy skin (10, 11), including that supplied by the saphenous nerve (58). However, C-mechanoreceptors are not found in the glabrous skin of the cat's foot pads (8, 11). The situation in monkey appears to lie, appropri ately, between cat and man. No C-mechanoreceptors are found in glabrous skin, but some are present in hairy skin, particularly on the proximal limb [T. Kumazawa and E. R. Perl, unpublished results cited by Burgess & Perl (27)]. These species and area differences may be correlated with the grooming behavior of the animals, since Bessou & Perl (10) noted that these receptors were ideal "bug" detectors. As noted above, additional quantitative data on input-output relations for Type II SA units has been provided by Chambers et al (30). The relation between increase· in firing frequency and static displacement has often fit a classic semilogarithmic relation (i.e. F A + K log S. where F frequency of nerve impulses, S =

=

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stimulus displacement. and A and K are constants). However, Chambers et al (30) also found that the data have often fit a power function (i.e. log F A + K log 5). The whole business of fitting functions to neural input-output is critically and perceptively reviewed by Kruger & Kenton (85). These authors showed how various normalization procedures, including corrections to exclude subthreshold parts of the input-output relations, can substantially alter the form of the best-fitting func tion.. Kruger & Kenton (85) also passed a critical eye over previous attempts to apply information theory to neural data, particularly attempts to assess channel capacity for SA cutaneous mechanoreceptors units (165). For exari,plc, they claimed (81, 85) that measured information transmission usually exceeds 4-5 bits if care is taken in assigning stimulus and response categories. Channel capacity must always exceed this figure and therefore earlier claims of equivalence between the channel capacity of single afferent neurones and that of human subjects in psychophysical tests (165) appear unjustified.


=

Central Connections of Mechanoreceptor A./ferents in Spinal Cord The pattern of connections made in the spinal cord by different types of afferents from the skin has been reviewed recently (15, 162, 163). In discussing spinal cord cells. I often refer to laminae 1-10; t hese are the cytoarchitectonic laminae of spinal gray matter described by Rexed (132). A detailed study of connections from myelinated afferents in the posterior femoral cutaneous nerve onto dorsal horn cells in decerebrate. spinal cats has been made by Tapper and his colleagues (19, 148). They studied only the hair receptors and touch corpuscles (Type I SA), and only those cells receiving short latency connections and lying in laminae 3-6. A few cells appeared to be excited by stimulation of just one receptor type (N.B. hairs were classified as G, G', and D, see above), although other cells rcccived a conv ergent input from all possible combinations of the four receptor types. The pattern of convergence over the population was not significantly different from what would be expected if all entering fibers made their connections indepen dently. However, only stimuli that would excite hair or touch corpuscle receptors were used, and many of these units may also receive input from higher threshold receptors and from heat-sensitive receptors (158. 159). In contrast to the independence of convergence of connections of different types, units showed a high degree of spatial interdependence. Thus when a unit received connections from receptors of more than one type, these always originated from the same skin area. Spinal cord cells examined by Tapper et al (148) had much larger receptive fields (30-80 times larger in area) than those of primary afferent units. The responses of dorsal horn cells to single spikes along single Type I axons were examined by Brown et al (21). The pattern of response of a given cell varied for different afferent fibers: some afferents produced short latency excitation followed by long latency inhibition, while others produced only excitation or only inhibition. Different cord cells were also tested from the same touch corpuscle, and again different effects were found on different cells. with no clear pattern emerging. It appears, therefore, that neither individual cells nor individual afferents have a stereotyped pattern of synaptic response. There were also no systematic variations



113

in the responses to stimulating single corpuscles at different distances from the centers of the receptive field for a cord cell. This contrasts with the effects of descending inhibition from the pyramidal tract, which is less effective on touch corpuscle input from the edge of the receptive field than on input from the field center (79). A series of papers on the location and properties of the cells of origin of the spinothalamic tract (STT) in both cat and monkey has established that many of these cells transmit information from skin mechanoreceptors (1, 41, 93, 94, 152, 153, 169). Spinal cord cells in the cat rarely send axons to the contralateral thalamus, and those that do are often situated deep in the spinal gray matter and do not receive excitation from cutaneous mechanoreceptors (93, 153). In the monkey, however, such cells are more plentiful and many are found in the first few laminae of the dorsal hom and are fired by sensitive cutaneous mechanoreceptors (94, 169). Willis et al (169) carefully characterized the responses of their cells to various sorts of stimuli, and related these responses to the anatomical location of the cells. Of their sample of STT cells, 38% were activated by gentle hair movement. These were mostly located in the lateral half of laminae 4 and 5. Responses to hair movement were rapidly adapting and receptive fields were often small, especially on the feet. Another 21 % of cells were excited by small skin movements, but not by hair movement. Some of these cells were tonically activated by maintained displace ments, while others adapted rapidly. Many of these STT cells, like other non-STT cells in the same region, were excited by noxious heating. Eighty dorsal horn neurones with axons in the spinocervical tract and terminating in the lateral cervical nucleus have been examined in the monkey lumbar spinal cord (22). These mostly responded to low threshold mechanical skin stimulation with a relatively rapidly adapting discharge. Their location lay predominantly in laminae 4--6. They did not differ much from nearby non-SCT cells, including presumably the STT cells described above. The monkey SCT thus closely resembles that of the cat, which had previously received most of the attention (15, 16). Connections of Mechanoreceptor Afferents in the Trigeminal Nucleus

A study of the responses following stimulation of the large sinus hairs (vibrissae) recorded from cells in the anterior part of the rat's trigeminal nucleus has revealed a considerable degree of specialization (143). Tonic (T) units were never excited from more than one vibrissa and showed marked directional sensitivity. No subdivi sion of T units is made by Shipley ( 143), but different illustrations show both a unit with marked dynamic firing (which resembles a Type I receptor) (55) and one with a linear displacement response like that found for Type II receptor units (55). However, it is not clear at present whether the cat classification can be carried over to rats. Phasic (P) units were also found in the rat trigeminal nucleus (143). These were often fired by movements of more than one vibrissa, unlike the primary afferents (170). Two types of phasic units were distinguished. One type (PS) had a low velocity threshold and fired steadily during constant velocity movements ( 143). The other type (PV) had a velocity-dependent threshold that was generally higher than for the PS units, but fired only one spike, or one brief burst of spikes, at the

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start of a constant velocity stimulus. These two types therefore bear a close resem

blance to the two RA types of receptor afferents found in cat, with the PV unit acting as though it received input only from Golgi-Mazzoni corpuscles and the PS unit resembling the other RA receptor unit with lower velocity threshold. PV units were the ones most commonly fired from more than one vibrissa. Usually a group of


adj acent vibrissae were effective, as found by Nord (117). In the cat, Mosso & Kruger (110) described only two types of cell excited by vibrissal movement in the caudal spinal trigeminal nucleus. One type had a low velocity threshold, was directionall y polarized, and som etimes showed tonic firing to a maintained displacement Another 33% of units responded to rapid hair move ments. Most spinal trigeminal units were only excited from one vibrissa (110).

Convergence of afferents from all types of hair within the receptive field onto cells in the cat in nuclei caudalis and oralis has been reported (137). I have found the literature on vibrissal units difficult to deal with as nearly every investigator has used different types of stimuli and different classification criteria. This has meant that potentially interesting comparisons about convergence onto central cells and about differences between species cannot be made. Apart from vibrissal units, a number of other cells driven by hair or skin move

ments were found in the caudal spinal nucleus in cat (110). Most appeared to be driven by only one afferent receptor type, according to a classification scheme like

(27). The degree of specialization of response patterns & Kruger (110) is striking, and extends to thermal and noxious

that of Burgess & Perl revealed by Mosso

stimuli. It is clearly important for the mechanoreceptor input running in the trigemi nal nerve from structures other than the vibrissae to be firmly established so that studies in the nucleus can have a firmer base. Surprisingly, we know more about trigeminal thermoreceptor afferents than about the mechanoreceptors. As well as finding a much higher degree of specificity than' in previous studies, Mosso

& Kruger (110) also found that many of the units that could be excited into

a slowly adapting discharge during a maintained skin displacement produced a very regular pattern of firing. A previous study by Darian-Smith et

al (38)

found only

rather variable firing by SA units in the caudal trigeminal nucleus. It seems likely that this difference may arise at least in part from the differing types of preparation used. The conclusion of Darian-Smith et al (38) and Darian-Smith (36) that the caudal part of the trigeminal nucleus had a very poor ability to transmit information about skin identation certainly seems premature in the light of recent findings

(I 10).

Mechanically Excited Units in the Dorsal Columns, Dorsal Column Nuclei; and Medial Lemniscus Most of the rapidly adapting cutaneous mechanoreceptor afferents with large myeli nated axons from monkey fore- and hindlimbs (166) and raccoon forepaw (131) send collaterals to upper cervical levels in the dorsal columns. This is similar to the

situation discovered earlier for cat (14,

15,

123). A

proportion of slowly adapting

afferents from the glabrous skin of the raccoon forepaw also project by this route (131), but none do so in the monkey (166). The raccoon is therefore more like the cat; since in the cat both Type I and II units project, at least in part, from the forelimb (155) and trunk (15).



115

Postsynaptic fibers ascending in both the dorsal columns and the dorsolateral funiculus to the dorsal column nuclei carry a wider range of information. Although usually excited by sensitive mechanoreceptors, they are also fired by high threshold receptors from both skin and, in the dorsal columns at least, muscle (40, 122, 154). Physiological and anatomical studies agree that postsynaptic fibers in both the DC and DLF terminate principally in rostral and basal parts of the nucleus and not on the "cell clusters" in the center of the nucleus where many of the primary afferent collaterals terminate (40, 53, 138, 149). A study of fibers in the medial leminiscus close to the thalamus has confirmed and extended earlier observations on the specificity of connections of cells in the DCN that project by this route (20). The bulk of axons fired spontaneously in the absence of stimulation, thus showing that this activity had not been caused by damage when it had been recorded in the DCN themselves. The bulk of axons had small forelimb receptive fields, sometimes restricted to one point only. Axons having fields restricted to one point, or in other cases to a few touch corp uscl es or a few tylotrich hairs, must receive a powerful input from only one receptor axon, thus indicating an amazing restriction of connections. Two important reviews on the dorsal column system have challenged classical assumptions about the role and organization of what was thought to be a system of secure relays carrying high resolution tactile information to the forebrain. Gor don (52) has stressed the anatomical and physiological complexity of the DCN. He pointed out that the discovery of inputs from outside the dorsal columns (see above) and of the descending effects from DCN onto spinal cord cells (19, 39, 40) make the interpretation of the effects of dorsal column lesions very difficult. Wall (161) has argued that the dorsal column-Iemniscal system does not function as a sensory relay at all. He has proposed that we look for a more sophisticated role for this system, and suggested that this role may be control of the activities of other input pathways such that optimal attention is paid to appropriate (e.g. changing) parts of the input. Wall & Dubner (163) have reviewed some of the more recent evidence on this matter. Since that review, Vierck (156) has shown that a long-lasting deficit of some nonexploratory tactile tasks can occur following dorsal column lesions. Monkeys were trained to discriminate the size of discs pressed against their feet. After a unilateral dorsal column (DC) lesion they could not make this discrimination for 70-90 days. After this period the performance gradually improved until at ) 20-) 80 days it was back to where it had been preoperatively. Vierck (156) also pointed out that the motor deficits recover over a similar, very long, time scale. Other tactile tasks (e.g. two-point discrimination) (95) recover much more quickly following DC lesions. None of the present hypotheses concerning DC function appear to be able to explain this difference between two very similar, passive, tactile tasks. An important finding reported by Wall (161) was that rats with only their dorsal columns intact did not behave as though they could feel stimuli applied distal to the lesion. Cats with very similar lesions have, however, recently been found to have normal thresholds

for electrical stimulation of mixed peripheral nerves below the completely incompatible. There

section (112). At first sight these two studies appear

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are, though, major differences in methods (e.g. different species; cutaneous test in one, electric shock to mixed nerve in the other; etc). In particular, it would be interesting to know if the cats of Myers et al (112) reacted to cutaneous stimuli of the type used by Wall (161) in a normal manner.


SKIN TEMPERATURE: WARM AND COLD Three useful reviews have been published recently by Hensel. Two deal with the structure and runction of cutaneous thermoreceptors (63, 64a) and one deals with the peripheral and central events involved in thermoregulation (64).

Afferent Thermoreceptor Units Responding to Skin Cooling A new attempt has been made to deter.mine the histological structure of the cold receptor by examining pieces of nose skin that have been shown electrophysiologi cally to contain such an ending (63, 64, 80). A characteristic nerve termination located in the most superficial layer of the dermis, and with fine processes in close contact with the basal cells of the epidermis, was found at the marked sites. The fine structure of these receptors has been examined using both light and 'electron microscopy (63). Attempts to locate warmth receptors using similar techniques have not yet proved successful (63). A number of recent studies have examined quantitatively the responses of primate cold receptors from tongue (125, 127, 128), face (44), and hand (36, 78, 98). Poulos & Lende (127, 128) recorded with a microelectrode in the trigeminal ganglion, while warming and cooling the tongue. They found many units responding to cooling and divided these into two classes, depending upon whether they responded to innocu ous mechanicarstimuli as well (T + M units) or not (T units). The majority of T + M units fired only when the temperature of the tongue was lowered fairly quickly. Another study of trigeminal afferent units found only T + M units, and most of these units gave slowly adapting mechanical responses (137, 142). It seems unlikely that such discharges play an important role in generating cold sensations (71, 78). The cold sensitivity of SA mechanoreceptors from limb skin has been studied quantita tively in cats (45) and monkeys (45, 78). The cold afferents from the glabrous skin of monkey hands have been studied using controlled cooling and warming pulses of short (usually 4 sec) duration (37, 78). Similar stimuli have been utilized for a parallel psychophysical study of thermal sensitivity in human glabrous skin (78). Conduction velocities of cold units from monkey hand ranged from 5-35 m/sec (average 15 m/sec); cold units with un myelinated fibers, such as have been found from primate hairy skin (65, 71), were not studied. Best static firing occurred at 19-31°C (average 25°C) and receptive fields were punctate. Moving the stimulator only 2 mm from the sensitive spot rendered the unit inexcitable even by a lOoC drop in skin temperature. Following rapid cooling, most, but not all, receptors gave a marked dynamic response that subsided over a few seconds as the unit adapted towards a steady firing fr�quency. This steady firing was characterized by the burst pattern described for some other cold units, particularly at low temperatures (37, 63, 71, 127). Stimulus repetition



117

rates of greater than 2-3/min gave rise to a cumulative depression of responsiveness, and the extent of this temporal depression was analyzed for pairs and triplets of cold "pulses" (37). Input-output relations for single fibers (37) and the variability of successive responses to a fixed stimulus (78) were also determined. The responses of primate cold receptors to heating the skin to noxious levels (above 45°C) have been examined for hairy skin of the face (44) and for glabrous skin of the hand (98). Facial cold receptors required heating to over 55°C initially before "paradoxical" firing (43) occurred, but were more sensitive on subsequent trials, with thresholds often dropping below 50°C (44). Immediately following the application of a heat stimulus, cold units fired little, but after a few seconds activity built up and could reach levels greater than those encountered during slow cooling (44). "Paradoxical" firing of cold units in glabrous skin of the hand was found to be markedly dependent upon rectal temperature (98). At a rectal temperature of 39°C, 90% of cold units were excited by skin heating to 53°C, while at 37°C rectal temperature only 20% of units fired for a similar stimulus. The mechanism by which cold-fiber heat sensitivity increases when rectal temperature rises is not clear. How ever, sympathetic effects may be involved. Recently it has been shown (146) that, in frogs, discharges in cutaneolls nerves following cooling are enhanced by sympa thetic stimulation or by local application of epinephrine or norepinephrine. It should be noted, however, that Long (98) found the "orthodox" (cold) excitation to be unaffected by rectal temperature changes. It is not clear whether glabrous skin units show any sensitization following noxious heating comparable to that found for units from facial hairy skin (44).

Afferent Thermoreceptor Units Responding to Skin Warming Many warmth fibers from monkey facial skin have been found to have thinly myelinated axons (44, 147), as have a very small number from glabrous skin of the monkey hand (37). This contrasts with all previously described warmth units that had unmyelinated axons (63). However, Sumino et al ( 147) pointed out that there is earlier evidence from psychophysical experiments using differential nerve block that warm sensations are due, in part at least, to activity in small 'myelinated axons (12). Recent studies of human sensations during pressure block, where the degree of block was monitored by nerve recording, have not examined this matter directly, but have confirmed that good warm sensations are still felt following moderate skin temperature rises even when all A fiber activity has been blocked ( 150). Facial warmth fibers, both those with myelinated and those with unmyelinated axons, showed good dynamic sensitivity ( 147). Their adapted firing could conform to one of two patterns. One group of warmth units reached peak firing frequencies at 4 1-42°C, while the other group fired best at a temperature above 45°C (44, 147). In contrast, nearly all warmth units isolated from the median nerve in the monkey and innervating glabrous skin had unmyelinated axons and few showed any dy namic firing (37, 89). A number of studies where microelectrodes have been used for recording from the trigeminal ganglion have failed to find any warmth units, although cold-sensitive units have been found (80, 127, 128, 137, 142). This is true even when areas h�ve

118

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been stimulated that are known to have warmth receptors [e.g. the tongue (42, 127, 128) and the nose (66, 80). In fact, all successful recordings from warmth fibers have been made by dissecting peripheral nerves, presumably because this technique al lows greater bias towards minority groups, particularly those with fine afferent fibers. It is important to realize that microelectrode samples from CNS structures may be as limited as those from the ganglion and thus not to make too much of negative results. Central Connections of Thermoreceptor A./Jerents

The presence of "specific" thermally sensitive units in the most superficial parts of the dorsal horn (lamina I, marginal zone) (31) has been confirmed by Hellon & Misra (59) in the rat. A similar concentration also occurs in the analagous pericor nual zone of the spinal trigeminal nucleus of the cat (47, 109, 110): Other cells excited. by small cutaneous temperature changes are also found in the deeper parts of the dorsal horn (59, 129) and spinal trigeminal nucleus (110). Thermal units in the trigeminal nucleus respond at relatively long latency' following electrical skin stimulation, thus indicating that they receive an input· only from afferents of fine caliber (110). Both ·"warmth" and "cold" units have been found in the trigeminaJ nucleus of the cat (47, 109; 110), and in the dorsal horn of monkey (35), cat (31), and rat (59). Warmth units appear to be relatively uncommon in the caudal spinal trigeminal nucleus (110). Thermal units were only found in the spinal nucleus and not in the main sensory nucleus of the trigeminal in anesthetized cats (47). Cold units in the monkey trigeminal nucleus showed a similar pattern of static and dynamic firing, as did afferent fibers isolated from the ganglion (125, 128a). The static firing profile of some spinal cord cells in response to skin warming also resembles that of primary afferents (67, 129). However, spinal cord units in rat often showed quite different static sensitivity profiles from those of afferents from the same skin area (the scrotum) (59, 71). For spinal cord cells, the relation between firing frequency and temperature was usually monotonic over the temperature range of 15-45°C (59); whereas the alferents showed the usual unimodal, convex relation with a maximum at 25-30°C (cold units) or 43°C (one;warmth unit) (71). Spinal cord warmth units also showed little dynamic firing following rapid temperature shifts, while cold units usually showed a good dynamic response (59). Trigeminal nucleus cold units also retained a good dynamic sensitivity like the primary afferents (125).. The degree of convergence from peripheral receptor units onto spinal cord cells is considerable in the rat, where most cells, including those in lamina I, had bilateral receptive fields (62). The receptive fields of cold units in the cat spinal trigeminal nucleus were much smaller, being only 2-4 mm across (47). However, given the dense innervation of cat facial skin and the punctate nature of peripheral receptive fields, this still indicates a considerable amount of convergence. The degree of convergence from lingual cold receptors onto trigeminal nucleus cells must also be considerable since the characteristic bursting pattern of the primary afferents was barely apparent in the discharges of such cells (125).


1 19

The projection pathways for thermal information are not clear, although cells similar to those found

in the trigeminal nucleus and spinal cord have also been found (60, 9 1 , 1 0 1 , 1 25, 1 26) and somatosensory cortex (6 1 , 90).

in ventrohasal thalamus

Axons in the anterolateral tract of the spinal cord at segments C3-5 have been found

respond to either skin cooling or warming of the trunk and hind limbs (144). These were assumed to be spinothalamic axons ( 1 44), although their termination was not tested directly. Direct spinothalamic axons are rare in the cat (152), and a recent study in the monkey of 1 8 6 spinothalamic cells identified by antidromic excitation from the thalamus revealed no specific thermosensitive units ( 1 69). Spe cific thermoreceptor units are not found in the spinocervical tract or the dorsal


that

columns ( 1 5), The central projection pattern for thermal information is likely

to be different

from those for other somatic systems because cutaneous thermoreceptors are in volved in thermoregulation in addition to their sensory role (64). One consequence of this duality is that information from cutaneous thermo receptors may be transmit ted to CNS neurons, which are themselves thermosensitive or are in receipt of information from thermosensitive neurones. Such a convergence has been shown for certain spinal cord cells

( 1 44).

NOXIOUS SKIN STIMULATION This section is restricted to considering the input from the skin. A more extensive review on these matters, including a consideration of the input from noncutaneous

somatic structures, is in preparation ( 1 00). Receptor Units HIGH THRESHOLD

MECHANORECEPTOR UNITS

Small myelinated afferent

fibers responding only to damaging or potentially damaging cutaneous stimuli have

been found with fields in hairy skin in cats (26) and in hairy and glabrous skin in monkeys ( 120). These units have distinctive receptive fields consisting of a number (3-20) of spots scattered over an area of 1-8 cm2 (26). Some of these units may also be heat sensitive (8,44), but possibly only after prolonged heating to noxious levels (27). It is not clear if the receptive fields of the units examined in recent studies consisted of multiple spots or whether they were in fact polymodal-type receptors with small myelinated axons like those described by Iggo & Ogawa (74) (see next section).

A small proportion of units with unmyelinated fibers are also excited by intense (8. 10). although they sometimes fire following extreme cooling ( 1 0, 27). These units may not comprise a homogeneous group since the form of their recepti ve fields is very variable. mechanical stimuli but not by noxious heat

POL YMODAL NOCICEPTOR UNITS

A large group of unmyelinated fibers re

sponding to strong pressure, noxious heating, and irritant chemicals was descFibed in

detail by Bessou & Perl (10) and designated as "polymodal nociceptor units."

Such units have a receptive field comprising one spot or small zone and have been

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found in cat hairy and glabrous skin (8, 10, I I), in primate skin (27, 44) including that of man ( 1 5 1 , 1 55a), in rat skin (75), and in rabbit skin (B. Lynn and E. R. Perl, unpublished observations). In monkeys, polymodal nociceptor units comprise about 90% of all unmyelinated afferent units (27) and are therefore the most numerous of all receptor units, at least from limb skin, since unmyelinated afferent fibers outnumber myelinated ones. And there are also some poIymodaI nociceptors with very slowly conducting myelinated axons (4-7 m/sec) in monkeys (74). Repeated heat ing increases the firing of polymodal nociceptors and reduces their heat threshold. This phenomenon was examined by Bessou & Perl (10) and was termed "sensitiza tion." Heat sensitization has also been reported for C-fiber units from the glabrous skin of the cat's foot pad (8) and for the paradoxical firing of cold receptors from monkey face with myelinated axons (44). Some polymodal nociceptors are excited by intra-arterial injections of bradykinin, others are excited by injections of serotonin (5-HT), and some respond to both (7). However, many other receptor units, including SA mechanoreceptors with large myelinated axons, mechanoreceptors with unmyelinated axons, and high threshold mechanoreceptors with A-delta axons and with C-axons were also excited by these substances. Only the RA hair units remain unaffected (7). Bradykinin, but not serotonin, was found to enhance the heat responses of C-fibers. These data are consistent with earlier work using intra-arterial bradykinin and serotonin (46) and intracutaneous bradykinin ( 1 0). SENSITIZATION AND SENSITIVITY TO IRRITANT CHEMICALS

RESPONSES OF MECHANORECEPTOR AND THERMORECEPTOR UNITS TO NOXIOUS STIMULATION A group of thermo receptors that have thresholds of

about 300e and increase their firing rate monotonically up to temperatures about

47°C have been described in the monkey face ( 1 47). This high optimum distin guished these units from many other warmth receptors, including others on the monkey face, which reach peak firing at temperatures below 45°C (44, 63, 1 47). Other warmth units with best static firing about 45°C have been described from the skin of the eat's nasal area (66). It has been suggested that the group with the high optimum temperature in monkeys may be involved with signalling threshold pain (44). However, it is not clear if the discharge of such units is maintained for more than a few seconds during noxious heating, or whether, like cat receptors, their discharges adapt out completely at high temperatures (66). The responses of a number of types of mechanoreceptors have been examined using both noxious and innocuous stimuli ( 1 1 , 1 20, 1 2 1). It was always possible to mimic the firing patterns produced by noxious stimulation with a large innocuous stimulus (27), and so these units are unlikely to play a role in generating painful sensations.

Central Connections of Nociceptor Afferents Cells in the most superficial layer of the monkey spinal cord (lamina 1 ; marginal cells) have been described that, like those originally found in the cat (3 1 , 83), only



12 1

respond to noxious cutaneous stimuli (86, 169). Similar cells are also found in the analogous pericornual zone of the caudal trigeminal nucleus of the cat ( l 09, 1 10). In both cat and monkey some of these cells send axons via the contralateral, lateral funiculus to upper cervical levels (86). In monkeys, but not in cats, many of these cells project all the way to the contralateral thalamus ( 153, 169). Some spinal cord cells situated deeper in the dorsal horn and in parts of the ventral horn and intermediate gray matter also respond to noxious mechanical or thermal stimuli, but not to innocuous stimuli (129, 169). Similar cells have also been found in the nucleus proprius of the caudal spinal trigeminal complex (82, 110). As well as these "specific" nociceptor cells, the dorsal horn contains a large population of cells that have low thresholds, but require noxious stimulation before maximal or maintained firing is produced (158). Such cells are concentrated in lamina 5 (68, 159) and 20% were found to send axons to the contralateral thalamus in monkeys ( 1 , 94). However, very few lamina 5 cells from cat lumbosacral cord project in this manner (93, 153), although more may do so from cervical cord (41). Axons of similar, wide-range neurons are also found in the spinocervical tract ( 16, 22) and in the dorsal columns ( 122). Many of these cells also receive input from muscle afferents and visceral afferents with small myelinated axons (Group III) ( 1 24, 1 4 1 ). Bradykinin, injected into a major limb artery, also produces vigorous firing in many lamina 5 cells (9). The evoked discharges of lamina 5 cells are markedly reduced by anesthetics ( 159). In spinal cats, nitrous oxide and hyperventilation were found to reduce the spontaneous firing of lamina 5 cells, but not that of lamina 1 cells (83). Spontaneous firing of neurons in the trigeminal nucleus that responded best to noxious stimuli was also inhibited by inhalation of 75% nitrous oxide, whereas the firing of cells that responded best to innocuous stimulation was enhanced (82).

CONCLUDING REMARKS This review has considered the somatosensory system in four parts, each concerned with a different stimulus set. There are many situations where interactions occur between these parts, and by treating the system in this manner, I am implicitly assuming a certain view of its organization ( 1 64). However, recent studies to a certain extent justify the approach adopted here. New examples of receptor specific ity have been found and the anatomical structures associated with many of these functional classes have been identified. Further, this work on the afferents is paral leled in recent finds concerning the specificity of responses of second-order neurones. Large numbers of cells that relay information to distant parts of the central nervous system do, however, receive an input from a wide spectrum of afferents, although the "width" of the spectrum may be considerably restricted in the presence of suitable activity in descending pathways ( 16, 79, 159). Undoubtedly situations like those existing in parts of the DeN, where one afferent fiber can dominate the output of some second-order cells, are the exception and there are no simple "relays" in the somatosensory system (52).

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Literature Cited 1 . Albe-Fessard, D., Levante, A., La mour, y. 1974. Origin of spino thalamic tract in monkeys. Brain Res. 65:503-9 2. Andres, K. H. 1 966. Uber die feinstruk tur der rezeptoren an sinushaaren. Z. Zell/orsch. 75:339-65 3. Andres, K. H., von Dureing, M. 1973. Morphology of cutaneous receptors. See Ref. 72, Chap. 1 , 1-28 4. Aoyama, M., Hongo, T., K udo, N. 1973. An uncrossed ascending tract ori ginating from below Clarke's column and conveying group I impulses from the hindlimb muscles in the cat. Brain Res. 62:237-41 5. Armett, C. I., Hunsperger, R. W. 1961. Excitation of receptors in the pad of the cat by single and double mechanical pulses. J. Physiol. London 1 5 8 : 1 5-38 6. Armett, C. J., Gray, J. A. B., Hun sperger. R. W., Lal, S. 1962. Transmis sion of information in primary receptor neurones and second order neurones of a phasic system. J. Physiol. London 1 64:395-42 1 7. Beck, P. W., Handwerker, H. O. 1974. Bradykinin and serotonin effects on var ious types of cutaneous nerve fibres. Pfluegers Arch. 347:209-22 8. Beck, P. W., Handwerker, H. 0., Zim mermann, M. 1974. Nervous outflow from eat's foot during noxious radiant heat stimulation. Brain Res. 67:373-86 9. Besson, I. M., Conseiller, C., Hamann, K. F., Mail lard, M. C. 1 972. Modifica tions of dorsal horn cell activities in the spinal cord, after intra-arterial injection of brady kinin . J Physiol London 22 1 : 1 89-205 10. Bessou, P., Perl, E. R. 1 969. Response of cutaneous sensory units with un myelinated fibers to noxious stimuli. J. Neurophysiol. 32: 1 025-43 1 1 . Bessou, P., Burgess, P. R., Perl, E. R., Taylor, C. B. 197 1 . Dynamic properties of mechanoreceptors with unmyelin ated (C) fibers. J. Neurophysiol 34: 1 1 6-3 1 12. Bishop, G. H. 1 960. The relation of nerve fiber size to modality of sensation. In Advances in Biology of Skin. ed. W. Montagna, Vol. 1 , 88-98. Oxford: Per gamon 1 3. Broda\, A., Pompeiano. O. 1957. The vestibular nuclei in the cat. J. Anat. 9 1 :438-54 14. Brown, A. G. 1968. Cutaneous afferent

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C-fiber mechanoreceptors of cat. Exp. Neurol. 33 :607-1 7 59. Hellon, R. F . , Misra, N . K. 1 973. Neu rones in the dorsal horn of the rat re sponding to scrotal skin temperature changes. J. Physiol London 232:375-88 60. Hellon, R. F., Misra, N. K. 1973. Neu rones in the ventrobasal complex of the rat thalamus responding to scrotal skin temperature changes. J. Physiol. Lon don 232:389-99 6 1 . Hellon, R. F., Misra, N. K., Provins, K. A. 1 973. Neurones in the somatosen sory corte1\. of the rat responding to scrotal skin temperature changes. J.

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Corticocortical connections of cat primary somatosensory cortex.

Intra- and interganglionic synaptic connections in the CNS of Aplysia.

Impulse activity and the patterning of connections during CNS development.

Anomalous atrio-ventricular connections and their features.

Catecholamine binding to CNS adrenergic receptors.

The somatosensory thalamus of monkeys: cortical connections and a redefinition of nuclei in marmosets.

Tectospinal and tectoreticular cells: their distribution and afferent connections.

Cytokines and their receptors.

CNS benzodiazepine receptors: physiological studies and putative endogenous ligands.

N-methyl-D-aspartate receptors and CNS symptoms of homocystinuria.

Corticocortical connections predict patches of stimulus-evoked metabolic activity in monkey somatosensory cortex.

Ontogeny of somatostatin receptors in the rat somatosensory cortex.

Synapses made by axons of callosal projection neurons in mouse somatosensory cortex: emphasis on intrinsic connections.

Opioid receptors and their biochemistry.

Teleost Chemokines and Their Receptors.

Protein hormones and their receptors.

Exosomes and their role in CNS viral infections.

Identified neurones isolated from leech CNS make selective connections in culture.

The potential of targeting NMDA receptors outside the CNS.

Localization of CNS glucoregulatory insulin receptors within the ventromedial hypothalamus.

Topography of connections between primary somatosensory cortex and posterior complex in rat: a multiple fluorescent tracer study.

Cysteinyl leukotrienes and their receptors; emerging concepts.

Gastrointestinal regulatory peptides and their receptors.

The natriuretic peptides and their receptors.