REVIEW ARTICLE THE DORSAL HORN OF THE SPINAL CORD

Quarterly Journal of Experimental Physiology (1982) 67, 193-212 Printed in Great Britain REVIEW ARTICLE THE DORSAL HORN OF THE SPINAL CORD A. G. BROWN Department of Veterinary Physiology, University of Edinburgh, Edinburgh EH9 JQH (RECEIVED FOR PUBLICATION 4 NOVEMBER 1981) CONTENTS PAGE (1) Introduction 193 (2) The frame of reference - Rexed's cytoarchitectonic scheme 194 (3) Input to the dorsal horn 195 Primary afferent fibres Anatomical specificity of axon collaterals The segregation of cutaneous input to the dorsal horn The somatotopic organization laid down by the primary afferent fibres Descending fibres from the brain The corticospinal tract The raphe-spinal system Reticulospinal pathways Propriospinal inputs (4) Neurones in the dorsal horn 202 Lamina I Lamina II (the substantia gelatinosa) Laminae III-VI (5) Connexions between laminae 204 Dendritic trees Axons and collaterals (6) Output from the dorsal horn 206 Marginal cells Spinocervical tract neurones Post-synaptic dorsal column neurones Neurones with axons ascending the dorsolateral funiculus Spinothalamic tract neurones Ventral spinocerebellar tract Output to the ventral horn (7) Summary 207 (8) References 208 INTRODUCTION The dorsal horn of the spinal cord and the dorsal column nuclei are the places where information from the body surface and underlying tissues reaches the central nervous system. It is here that the first stage in the integration of sensory messages takes place, where the major somatosensory systems originate and the first place where the brain can exert 7 EPH 67

194 A. G. BROWN control over the messages through a variety of descending pathways. IModern research on the dorsal horn may be considered to have a history of about 30 years, from the introduction of Rexed's cytoarchitectonic scheme (Rexed, 1952, 1954), the electrophysiological experiments using micro-electrodes (Hagbarth & Kerr, 1954; Kolmodin, 1957, Kolmodin & Skoglund, 1960; Eccles, Eccles & Lundberg, 1960; Wall, 1960; Armett, Gray & Palmer, 1961), the introduction ofelectron microscopical studies (Gray, 1963; Kerr, 1966; Ralston, 1968a, b; Rethelyi & Szentaigothai, 1969), the renaissance of silver staining (Scheibel & Scheibel, 1968; Sterling & Kuypers, 1967a, b; Matsushita, 1969) and modern degeneration studies (Szentaigothai, 1964). During the past 10 years the pace of research has quickened and is accelerating. Micro-electrode techniques and electron microscopy have been refined and new methods introduced, for example: autoradiography and retrograde and orthograde transport methods for tracing pathways and neuronal connexions, intracellular staining techniques that allow the anatomy of electrophysiologically recorded neurones to be studied, and powerful histochemical and immunocytochemical methods for localizing transmitters and their receptors. There is now a powerful armamentarium of methods for neuroscientists to use and their use has converged on the dorsal horn of the spinal cord, not least because of its important role in pain mechanisms. The present review is intended to provide an account of the organization of the dorsal horn of the spinal cord for the general reader and I hope it will be of use for teaching purposes. Anyone requiring more detailed accounts is referred to Willis & Coggeshall (1978) and Brown (1981). THE FRAME OF REFERENCE - REXED S CYTOARCHITECTONIC SCHEME For present purposes the dorsal horn of the spinal cord is defined as that part of the spinal grey matter dorsal to the central canal. This definition leads to the inclusion of what has been called the intermediate zone by several authors (see also Rethelyi & Szentaigothai, 1973; Rethelyi, 1976) but is the definition used by Rexed and it has turned out to be most appropriate when the cutaneous nerve input to the cord is considered. In Rexed's (1952, 1954) scheme the dorsal horn is divided into six layers or laminae based on the cytoarchitectonics of the region as viewed in 100,um thick Nissl stained sections of cord. That is, the scheme is based on the shapes, sizes, density and distribution of neuronal cell bodies. The locations of the laminae are shown in Figs. 5 and 7 for the seventh lumbar segment in the cat. Details of the cellular constituents of the various laminae will be given below; here a general description will relate the laminae to other descriptive terms. Lamina I is the most dorsal layer and runs around the dorsal and about half the lateral edge of the dorsal horn. It is the thinnest of all the layers and contains the marginal cells described by Waldeyer (1888). Lamina II follows next and is equivalent to the substantia gelatinosa Rolandi. Although there has been some controversy in the past about whether or not the next deeper lamina (III) should be included in the substantia gelatinosa (see Szentaigothai, 1964; Ralston, 1965; Sterling & Kuypers, 1967 a; Scheibel & Scheibel, 1968; Rethelyi, 1977) Rexed was of the opinion that only lamina II was the gelatinous substance of Rolando and at a recent symposium under the auspices of the Somatosensory Commission of the International Union of Physiological Sciences it was agreed that lamina II and the substantia gelatinosa are one and the same (see Brown & Rethelyi, 1981; for a recent detailed discussion of the 'naming of parts' see also Cervero & Iggo, 1980). Lamina II is thicker than lamina I and

DORSAL HORN 195 can be divided into inner (IIi) and outer (IIO) zones; like laminae I and III it runs around the lateral border of the dorsal horn to about half way down the lateral edge. Lamina III is thicker than the two more dorsal layers and its cells are slightly larger and less tightly packed (there are some neurones too in this layer). It corresponds with the dorsal part of the nucleus proprius of classical literature. Lamina IV is thicker still and runs from the medial edge of the horn to where the ventral bend of the upper three layers runs down the lateral edge. Cells are of varying sizes in this layer and a few very large neurones are present. Layer IV forms the ventral part of the nucleus proprius and with lamina III is the 'head 'of the dorsal horn. Laminae V and VI extend straight across the dorsal horn from medial to lateral edges and correspond respectively with 'neck' and 'base' of the horn in older literature. It is possible (Rexed, 1952) to divide each of these two layers into medial and lateral regions. This scheme of Rexed's is, then, our frame of reference. Although it is a scheme based purely on cytoarchitectonics and the distinction between some of the layers is not particularly clear it is a surprisingly successful scheme. It will be shown below that inputs to the dorsal horn, from both primary afferent (dorsal root) axons and from axons descending from the brain often respect the cytoarchitectonic boundaries, as do a considerable number of the dendritic trees of dorsal horn neurones. INPUT TO THE DORSAL HORN Primary afferent fibres Classical and modern neuroanatomical techniques have, of course, provided much useful information about the way primary afferent fibres enter the spinal cord and branch therein. Unfortunately, no anatomical method per se is capable of identifying the axons in terms of the receptors they innervate except crudely as cutaneous vs. muscle. The introduction (Brown, Rose & Snow, 1977) of a method for the injection of horseradish peroxidase (HRP) into single axons from an intra-axonal micro-electrode has allowed a new level of analysis to be achieved; the micro-electrode may be used for recording from the axon and therefore its physiological response properties may be determined and subsequent histochemistry provides both light and electron microscopical material for anatomical study. The larger myelinated cutaneous and muscle afferent fibres have been studied in the author's laboratory (Brown et al. 1977, 1978; Brown, Fyffe & Noble, 1980; Brown, Fyffe, Rose & Snow, 1981; Brown & Fyffe, 1978, 1979; Fyffe, 1979, 1981) and some smaller myelinated cutaneous and subcutaneous afferents by Perl and his collaborators (Light & Perl, 1979; Mense, Light & Perl, 1981). Some general principles of the organization of this primary afferent input to the dorsal horn are now apparent. Anatomical specificity ofaxon collaterals. The most striking result of these recent studies is that the branching pattern of the collaterals arising from the axons after they enter the spinal cord is quite specific and varies according to the type ofafferent unit. These differences are shown in Fig. 1 for the large myelinated axons innervating sensitive cutaneous mechanoreceptors and in Fig. 2 for smaller myelinated axons. All types have specific branching and bouton distribution patterns and there are limitations to the bouton distribution that respect laminar boundaries. Thus hair follicle afferent fibres (Figs. 1 A, B and 2A) have collaterals that form the 'flame-shaped arbors' when viewed in transverse sections (Scheibel & Scheibel, 1968) and their boutons are distributed mainly to lamina III; only an occasional bouton may be seen in lamina IIi and relatively few in dorsal lamina IV. 7-2

196 A. G. BROWN A B I ( C 4- I-; D E F G -/4$ H J Fig. 1. Summary diagrams of the organization of axon collaterals from cutaneous afferent fibres in the cat's lumbosacral spinal cord. The column of figures on the left shows reconstructions of representative collaterals; the column on the right shows three-dimensional representations of the different types. A, B, hair follicle afferent; C, D, rapidly adapting (Krause) mechanoreceptive afferent; E, F, Pacinian corpuscle afferent; G, H, slowly adapting Type I afferent; I, J, slowly adapting Type II afferent. (From Brown et al. 1981.)

DORSAL HORN 197 A B NP 1 1l00o,m Fig. 2. Collaterals from cutaneous afferent fibres. A, Collaterals from an axon innervating a D hair follicle receptor in cat. Note the similarity to Fig. 1 A, B. B, a collateral from an axon innervating a cutaneous high-threshold mechanoreceptor in monkey. NP, nucleus proprius; MZ, marginal zone; SG, substantia gelatinosa; the arrows indicate the ventral border of substantia gelatinosa. (From Light & Perl, 1979.) The other cutaneous axons have collaterals with a rather wider distribution as indicated in Fig. 1 B-J. Myelinated axons innervating sensitive mechanoreceptors distribute their axons to some or all of laminae III, IV, V and the dorsal part of VI. There is no input from these axons to lamina I nor to lamina II; only an occasional bouton is seen in lamina IIi. Myelinated axons innervating nocireceptors send their input to laminae I and sometimes into lamina V also (Light & Perl, 1979). The dorsal horn receives primary afferent fibre inputs from muscle, joint and visceral nerves as well as from cutaneous ones. Only muscle afferent fibres have been examined in detail. Group I a axons from the primary endings in muscle spindles distribute collaterals to lamina VI (and, of course, to lamina VII where the Ia inhibitory interneourones are

198 A. G. BROWN A B I 1 mm II I I mm C 1 mm E F Fig. 3. As Fig. 1 [, /, II 1 mm but summary diagrams of muscle afferent fibre collaterals. A, B, Group Ia muscle spindle afferent; C, D, Group Ib tendon organ afferent; E, F, Group II muscle spindle afferent. located (Jankowska & Lindstrom, 1972), and to lamina IX, the motor nuclei of the spinal cord - see Fig. 3 A, B). Group II axons from secondary endings in muscle spindles also distribute to the deeper regions (laminae VII and IX) and also have collaterals to the dorsal horn in laminae IV-VI (Fig. 3 E, F). Group Ib axons from the Golgi tendon organs distribute their input to a wide region in laminae V-VII which therefore includes the lower two laminae of the dorsal horn (Fig. 3 C, D). As shown in the Figures the muscle afferent fibres also have collaterals with specific branching patterns. The segregation of cutaneous input to the dorsal horn. As mentioned above, cutaneous afferent fibres innervating sensitive mechanoreceptors and with large (Aa-y) myelinated axons distribute their input to laminae III-VI in the dorsal horn: they do not give boutons to lamina I or to lamina II, except very occasionally to the innermost part of II (lamina

DORSAL HORN 199 III). Furthermore, the thinner (Ad) cutaneous axons innervating hair follicle receptors also distribute their input in the same way as their thicker brethren that innervate hair follicle receptors. Within the Ad group of axons (Group III in Lloyd's, 1943, nomenclature) are some that innervate cutaneous and deep nocireceptors. They have been shown, by intra-axonal HRP injection (Light & Perl, 1979; Mense, Light & Perl, 1981) to provide synaptic boutons to lamina I, the marginal cell layer. In addition these afferents innervating high threshold mechanoreceptors may send terminals to lamina V. Non-myelinated (C) fibres have not been injected with HRP and evidence on their projection to the spinal cord comes from less direct techniques. Rethelyi (1977) suggested, on the basis of Golgi material, that fine, probably non-myelinated, axons were distributed to lamina II, the substantia gelatinosa. Degeneration and autoradiographic studies (LaMotte, 1977; Ralston & Ralston, 1979) also showed probable C fibre terminations in lamina II. Finally, substance P (which is considered by some to be the putative transmitter in small axons) is localized mainly in laminae I and II (Hockfelt, Kellerth, Nilsson & Pernow, 1975; Takahashi & Otsuka, 1975; Chan-Palay & Palay, 1977; Pickel, Reis & Leeman, 1977). Non-myelinated axons innervate a variety of receptors, many of which are sensitive mechano- or thermoreceptors, and the nocireceptors do not have an exclusive claim to afferent C fibres. It remains to be seen whether there are differences in the projections of the different types of C afferent unit. However, Light, Trevino & Perl (1979) on the basis of the response properties and dendritic distribution of neurones within laminae I and II have suggested that C fibres innervating sensitive mechanoreceptors project to inner lamina II (IIi), whereas those innervating nocireceptors (and thermoreceptors in primates) project to outer lamina II (II) and lamina I. Obviously such reasoning is indirect and depends on the assumption that the input is monosynaptic in order for it to be substantiated. Such an explanation, however, seems the most likely one at present. The somatotopic organization laiddown by theprimary afferentfibres. When micro-electrode recordings are made from neurones in the dorsal horn it is apparent that the receptive fields of the neurones form a map of the body surface. This map, which is a second order map, is a reflexion of the map laid down by the primary afferent fibres within the dorsal horn. This primary map cannot be revealed by electrophysiological means nor, at the single fibre level, by anatomical methods. The pooling of data from experiments in which single cutaneous axons are injected with HRP shows that the map recorded from dorsal horn neurones and the map laid down by the primary afferent fibres are similar, irrespective of any possible differences due to selectivity of connexions or the sampling by neurones ofinput from a number of primary afferent fibres. The second order map is shown in Fig. 4 for the lumbosacral enlargement of the cat. It is immediately apparent that the map consists of a series of crescentric shells surrounding a large medial area containing the representation of the toes. Surrounding the toe area are shells for the foot, then the leg and, most laterally of all, the thigh and hip. 1 he map has a steep gradient mediolaterally and a gentle gradient rostrocaudally. These gradients reflect the fact (see Figs. 1-3) that primary afferent fibres form long sagittally running columns of terminals within the dorsal horn; the columns may run for at least 1 cm up and down the length of the cord. Descending fibres from the brain The dorsal horn, in addition to receiving inputs from primary afferent fibres entering via the dorsal roots, also receives inputs from neurones located at various sites in the brain. For the purposes of the present review corticospinal, raphe-spinal and reticulospinal

200 A. G. BROWN L 5 Med. Ieg Med. foot L L D a a 0 T M e e e Illr sra e F f I 0 L 7 e 0 IV \thigh Prox. med.' thigh ()0 Perineum tail Fig. 4. Schematic diagram of the somatotopic representation of hind limb skin in the lumbosacral spinal cord of the cat (Modified from Brown, Fyffe, Noble, Rose & Snow, 1980.) systems will be considered but these, of course, do not represent the only descending fibre systems. Their termination sites are shown in Fig. 5. The corticospinal tract terminates widely in laminae III-VI or even VII (Nyberg-Hansen & Brodal, 1963). Corticospinal fibres arising in classical sensory areas terminate more dorsally than those arising from classical motor areas (Nyberg-Hansen & Brodal, 1963; Coulter & Jones, 1977). Corticospinal terminations are absent from laminae I and II. Activation of the corticospinal tract leads to a number ofeffects in the dorsal horn. There is primary afferent depolarization (Carpenter, Lundberg & Norrsell, 1963a; Andersen, Eccles & Sears, 1964) indicating the operation of presynaptic inhibition, and this is powerful on cutaneous afferent fibres, and inhibition or excitation of various dorsal horn neurones including those giving rise to ascending pathways (Wall, 1967; Fetz, 1968; Brown & Short, 1974; Coulter, Maunz & Willis, 1974). The raphe spinal system arises from the mid-line raphe nuclei of the brainstem and consists of bilateral pathways descending in the dorsolateral funiculi. Terminations are in laminae I and II and in lamina V and medial parts of laminae VI and VII (Basbaum & Fields, 1977; Basbaum, Clanton & Fields, 1978). Laminae III and IV are spared. It is significant that

DORSAL HORN 201 [1 Corticospinal " (sensory cortex) E Corticospinal (motor cortex) [ Raphe-spinal E Reticulospinal (N. reticularis magnocellularis) M Reticulospinal (N. reticularis gigantocellularis) Fig. 5. Diagrammatic representation of the terminal areas of various descending systems in the lumbosacral spinal cord of the cat. (From Brown, 1981.) the parts of the dorsal horn receiving input from the raphe nuclei are those parts considered to be concerned with nociception and to give rise to spinothalamic and spinoreticular tracts. The descending fibres from the raphe nuclei contain serotonin (Dahlstrom & Fuxe, 1965) and ionophoresis of serotonin onto dorsal horn neurones leads to depression oftheir activity (Engberg & Ryall, 1966; Randic & Yu, 1976). Also electrical stimulation of the nucleus raphe magnus leads to primary afferent depolarization (Proudfit & Anderson, 1974) and inhibition of dorsal horn neurones (Basbaum, Clanton & Fields, 1976; Fields, Basbaum, Clanton & Anderson, 1977; Guilbaud, Oliveras, Giesler & Besson, 1977) including cells of origin of the spinothalamic tracts (Beall, Martin, Applebaum & Willis, 1976; Willis, Haber & Martin, 1977). Reticulospinal pathways include the raphe-spinal system but in addition other pathways descending from the brain stem to the dorsal horn. Basbaum et al. have shown by means of autoradiography that a pathway arising in the nucleus reticularis magnocellularis descends in the ipsilateral dorsolateral part of the spinal cord (and also more ventrally) and terminates in similar regions to the raphe-spinal system, i.e. in laminae I, II, ankd~~d in addition it also terminates in lamina VII in the ventral horn. Thi:-'

202 A. G. BROWN mono-aminergic and is presumably responsible for the tonic descending activity that inhibits many dorsal horn neurones and spinal reflexes in the decerebrate preparation and produces primary afferent depolarization (Holmqvist & Lundberg, 1959, 1961; Holmqvist, Lundberg & Oscarsson, 1960; Carpenter, Lundberg & Norrsell, 1963 b; Engberg, Lundberg & Ryall, 1968 a-d). Another descending system arising fron Nucleus reticularis gigantocellularis terminates mainly in the ventral horn, in laminae VII and VIII (Basbaum et al. 1978). Propriospinal inputs Less is known about propriospinal inputs to the dorsal horn than either primary afferent inputs or those from the brain. This is because short-ranging connexions are much more difficult to study with presently available techniques. Lissauer's tract, situated at the dorsolateral bend of the dorsal horn, consists of small myelinated and, mainly, nonmyelinated axons, two thirds of which are of primary afferent origin (Chung, Langford, Applebaum & Coggeshall, 1979; Chung & Coggeshall, 1979). The remaining one third of fibres arises from dorsal horn neurones, most of which are either marginal cells of lamina I or neurones in lamina II. These axons are propriospinal and run for short distances in Lissauer's tract (from a few millimetres to several cord segments according to different reports) connecting laminae I and II at different levels. According to LaMotte (1977) there are some Lissauer tract fibres that terminate in lamina III. Axons of ascending pathways may give off collaterals (in the white matter) that enter the dorsal horn. This has been seen for axons of both spinocervical tract neurones and also neurones belonging to the post-synaptic dorsal column system (Brown et al. 1977; Brown & Fyffe, 1981). Almost nothing more is known about propriospinal links between dorsal horns at different levels, but there must be both ascending and descending connexions. The marginal cells of lamina I seem prime candidates for a role in intersegmental connexions (Burton & Loewy, 1976) NEURONES IN THE DORSAL HORN Lamina I The most conspicuous occupants of lamina I are the marginal cells although there are other small neurones about which little is known. The marginal cells (Fig. 6) have dendritic trees that are disc-like in their envelope and generally confined to lamina I itself (Gobel, 1978 a; Light et al. 1979; Price, Hayashi, Dubner & Ruda, 1979). Marginal cells are usually excited by noxious stimulation of the skin (Christensen & Perl, 1970) although a minority appear to be excited by sensitive thermoreceptors (Iggo & Ramsey, 1976; Kumazawa & Perl, 1978; Light et al. 1979) and according to the last named authors such cells have dendrites that enter lamina II. Lamina II (the substantia gelatinosa) The small neurones of lamina II have been studied extensively in recent years. Unfortunately on both the structural and functional fronts these recent investigations have produced ~. rather confusing results. For a detailed review, and the views of one group, the reader is o4 Cervero & Iggo (1980). Anatomically the classification of neurones proposed,cajal (1909) still stands the test of time: there are two main types of cells,

DORSAL HORN 203 Fig. 6. Diagrammatic representation of the dendritic tree organization in the dorsal horn. The drawing is meant to show the organization as viewed in a parasagittal block of tissue. I, islet cell of lamina II; M, marginal cell of lamina I; P, pyramidal cell of lamina III; PSDC, the three main types of neurones sending axons through the dorsal columns; S, stalked cell of lamina II; SCT, spinocervical tract cells; X, Y, Z, interneurones of laminae V and VI. (From Brown, 1981.) the central cells and limiting cells (these have been called islet cells and stalked cells respectively by Gobel, 1975, 1978 b). Central (islet) cells have very small cell bodies (7-14 #sm diameter) and are situated in the inner part of lamina II; their dendritic trees are well developed in the rostrocaudal plane of the cord but restricted in the mediolateral and also the dorsovental axis where the tree is usually confined to lamina II (Fig. 6). Limiting (stalked) cells have their soma in outer lamina II near or at its junction with lamina I. Their dendritic trees are cone-shaped and descend from the cell body into lamina II, sometimes being confined to II. but sometimes running into IIi (Fig. 6). Electrophysiological recording from lamina II neurones has only a recent history. Undoubtedly, these neurones are more difficult to record from than many others but the differences in results obtained by the different groups cause concern. Part of the difficulty is due to the relatively small sample of recordings from neurones that have been definitely established as located in lamina II (only intracellular staining can provide that sort of evidence) and to the use of different preparations (anaesthetized, spinal or decerebrate preparations) and different types of micro-electrodes. Also, the different groups obviously classify the response of the units according to different criteria and one group (Cervero, Iggo & Molony, 1979) classifies the response in terms of inhibitory input to the cells whereas all other groups classify their cells on the basis of excitatory responses. All groups (Light et al. 1979; Bennett, Abdelmoumene, Hayashi & Dubner, 1980; Cervero et al. 1979; Molony, Steedman, Cervero & Iggo, 1981; Wall, Merrill & Yaksh, 1979) have recorded neurones responding exclusively to noxious stimuli and Light et al. and Bennett et al. agree that such neurones have their dendrites limited to the outer part of lamina II. All groups report neurones responding only to innocuous mechanical stimulation I I I

204 A. G. BROWN of the skin and most groups (the exception is Perl's group - Light et al. 1979) report neurones responding to both noxious and innocuous inputs. These two sentences sum up the similarities between the various studies and to the casual reader this may seem like total agreement. However, detailed examination of the original papers shows that there are marked differences in the proportions of the different types and, in the detailed receptive characteristics (Perl's group for example, deny the existence of 'wide dynamic range' neurones and neurones with input from large myelinated fibres as described by Price et al. 1979, Bennett et al. 1980, and Wall et al. 1979). Furthermore, although most groups report the presence of cells showing what might be called 'unusual' properties like habituation prolonged discharges and off-responses, Iggo's group insisted on excluding all cells unless they showed 'novel responses'. Obviously lamina II neurones are both structurally and functionally heterogeneous; lamina II is not a single entity and will not yield its secrets easily, and certainly not while the main research groups are using so many different sets of criteria to describe the cells and their responses. Laminae III- VI The remaining laminae can be considered together, not because they form anything like a structural or functional entity (far from it) but because the neurones have dendrites that cut across these laminae and because several major ascending systems arise from cells whose somata lie within them. However, it may be that to some extent lamina III is a zone of transition between lamina II and the deeper layers. Lamina III contains a large number of small neurones about which little is known at present; some of them have properties similar to lamina II neurones according to Wall et al. (1979). Many cells in lamina III, including some of the smallest, have dendritic trees that extend dorsally through lamina II and into lamina I where they run around the dorsal and dorsolateral border of the dorsal horn (Fig. 6). Some of these neurones also have ventrally directed dendrites that ramify in laminae IV and V. Such neurones can obviously receive their input from wide areas of the dorsal horn (laminae I-V). The dendritic tree organization within laminae III and IV is varied. Some neurones, especially those of the spinocervical tract, have dendrities that tend to run in the long axis of the cord producing dendritic trees that are elongated in this direction; others, such as those of the post-synaptic dorsal column system, have more or less cylindrical dendritic trees running dorso-ventrally. The boundary between laminae II and III is observed by the dendrites of spinocervical tract cells, whereas those of the post-synaptic dorsal column system and many other neurones, do not respect this boundary. Within the laminae V and VI there is a more general orientation of dendritic trees. Nearly all neurones, whether belonging to ascending pathways such as the post-synaptic dorsal column system or not, have dendritic trees that form transverse plates or cylinders. CONNEXIONS BETWEEN LAMINAE Within any one transverse plane of the dorsal horn there are connexions between the various laminae (Figs 6 and 7). These can be viewed from both the input and output sides, i.e. the dendritic trees and the axonal projections of neurones. Dendritic trees Within laminae I and II both marginal cells and cells of the substantia gelatinosa tend to have dendrites that respect the laminar boundaries in which their somata are located.

DORSAL HORN 205 Fig. 7. Diagrammatical representation of the axonal projections of dorsal horn neurones. DLF, neurone sending its axon through the dorsolateral funiculus but not terminating in the lateral cervical nucleus; I, islet cells of lamina II; Int, interneurones with short axons; M, marginal cells of lamina I; PSDC, cells of the post-synaptic dorsal column pathway; S, stalked cells of lamina II; SCT, spinocervical tract neurones; STT, spinothalamic tract neurones. (Modified from Brown, 1981.) This is by no means an exclusive feature; there are enough dendrites crossing the I-II and 11-III borders to make absolute segregation of input to laminae I and II impossible. As mentioned in the preceding section many lamina III neurones collect information from a wide area of the dorsal horn - from laminae I to V or even VI. Likewise, neurones with their somata in laminae IV, V and VI do not have dendritic trees limited to their own lamina. It is obvious that no matter how segregated primary afferent and descending input might be, many neurones (perhaps the majority) are capable of sampling inputs from wide areas. Axons and collaterals Many neurones of the dorsal horn have short axons that do not project beyond a few millimetres at most; others, even though they might belong to an ascending pathway, have local actions through axon collaterals. The general arrangement of local (and projecting) axons is shown in Fig. 7. Many marginal cells of lamina I have axons that project for long distances (see below) but it seems likely that there are local connexions with other lamina I neurones via short axons or collaterals and also via Lissauer's tract (SzentaLgothai, 1964; Scheibel & Scheibel, 1968; Narotzky & Kerr, 1978). There is good evidence that limiting cells of lamina II send their axons into lamina I (Gobel, 1975, 1978b; Bennett et al. 1980). Central cells of lamina II, on the other hand, appear to have axons that remain within lamina II and indeed remain within the vicinity of the cell's dendritic tree (Gobel, 1975, 1978b; Bennett et al. 1980). With laminae Ill-V most neurones, even those whose main axon projects out of the grey matter, have axonal projections that are directed to deeper laminae. They may thus form the anatomical basis of Wall's (1967) cascade hypothesis wherein the cells in progressively deeper laminae from IV onwards excite each other in tum. These ventrally directed connexions are also usually arranged so that they lie underneath the soma of their parent

206 A. G. BROWN neurone, thus maintaining the dorsoventral columnar arrangement of the dorsal horn and not smearing, to any great extent, the somatotopic organization laid down by the primary afferent fibres. OUTPUT FROM THE DORSAL HORN Marginal cells The marginal cells oflamina I must be considered important output neurones of the dorsal horn and probably the majority of these cells have axons that project to distant parts (perhaps single cells have multiple projections). Marginal cells have been shown to project to many targets: (1) the spinal cord a few segments caudally or rostrally (Burton & Loewy, 1976); (2) the lateral cervical nucleus (Craig, 1978; Brown, Fyffe, Noble, Rose & Snow, 1980), and they may therefore be considered to form part of the spinocervical tract; (3) the medullary and mid-brain reticular formation and probably the dorsal column nuclei (Trevino, 1976; Molenaar & Kuypers, 1978); (4) the thalamus (Trevino & Carstens, 1975; Carstens & Treveno, 1978; Giesler, Menetrey & Basbaum, 1979; Willis, Kenshalo & Leonard, 1979), and thus they form part of the spinothalmic tract - in both cat and primate species; (5) to the cerebellum in cats and monkeys but apparently not in rats (Snyder, Faull & Mehler, 1978) and therefore form some component of at least one of the many spinocerebellar pathways. These observations raise interesting questions about the possible roles of marginal cells, especially in view of the fact that most of them are excited by noxious stimuli. Should they be considered as a heterogeneous group of neurones contributing to different, and often specific, pathways, or should they be thought of as part of a general system with some general function on a wide variety of targets? This latter position seems the more satisfactory to the present writer. Spinocervical tract neurones The spinocervical tract (see Brown, 1973, 1981, 1982, for reviews) arises from dorsal horn cells and terminates in the lateral cervical nucleus in the upper cervical cord. It is a major somatosensory pathway in many species and is present in primates. The neurones are located in laminae III (30%), IV (60%) and V (10%) and their axons ascend the cord. in the most medial and superficial parts of the dorsolateral funiculus ipsilateral to the location of the cells. The spinocervical tract carries information about light touch and noxious mechanical and thermal stimuli. In the cat it does not carry information from sensitive mechanoreceptors in glabrous skin (Pacinian corpuscles, Krause corpuscles or Type I slowly adapting receptors) nor from the sensitive Types I and II slowly adapting mechanoreceptors in the hairy skin. Post-synaptic dorsal column neurones The presence of second order axons in the dorsal column has been recognized for a long time but the magnitude of this projection has only recently become apparent (about 10-15 % of axons projecting from lumbosacral dorsal columns to the dorsal column nuclei are not primary afferents (Angaut-Petit, 1975). The post-synaptic dorsal column system, in the cat, therefore has about the same number of neurones as the spinocervical tract. It seems likely that the situation is similar in the monkey (Rustioni, 1977). Post-synaptic dorsal column neurones are located in laminae III, IV and the medial parts

DORSAL HORN 207 of V, in about the same proportions in the different laminae as spinocervical tract cells. The axons of the cells enter the dorsal columns through the dorsal or medial border of the dorsal horn, and some neurones even send their axons initially into the ipsilateral dorsolateral funiculus before traversing the dorsal horn to enter the dorsal columns (Brown & Fyffe, 1981). The post-synaptic dorsal column pathway carries similar information to the spinocervical tract, in addition it also forwards input from the sensitive mechanoreceptors in both hairy and glabrous skin that do not excite spinocervical tract neurones. It is perhaps worth stressing that not all post-synaptic dorsal column neurones are excited by all the various inputs; some respond only to certain sensitive mechanoreceptors, whereas others show various degrees of convergence from sensitive and insensitive receptors. Neurones with axons ascending the dorsolateralfuniculus There is a class of neurones that sends its axons beyond the lateral cervical nucleus. The axons run in the ipsilateral dorsolateral funiculus and the parent neurones are mainly in lamina IV. The targets of these axons are not known with any precision but probably include the dorsal column nuclei (Dart & Gordon, 1973; Rustioni & Molenaar, 1975; Craig, 1978). Spinothalamic tract neurones Some marginal cells project to thalamic nuclei. In the cat some occasional cells in laminae IV, V and VI project to the thalamus, but most are in the ventral horn in lamina VII (Carstens & Trevino, 1978). In primate species the neurones are in similar places but, in addition, there is a well developed cluster of cells in lateral laminae IV and V (Trevino, Coulter & Willis, 1973). Spinothalamic tract neurones respond to a wide variety of inputs including those activated by sensitive mechanoreceptors as well as nocireceptors (Willis, Trevino, Coulter & Maunz, 1974; Applebaum, Beall, Foreman & Willis 1975; Willis, Maunz, Foreman & Coulter 1975; Kenshalo, Leonard, Chung & Willis, 1979). Ventral spinocerebellar tract Ventral spinocerebellar tract neurones are located in the lateral parts of laminae V, VI and VII (Eccles, Hubbard & Oscarsson, 1961; Hubbard & Oscarsson, 1962; Jankowska & Lindstrom, 1970). These neurones do not extend more caudally than the L6 segment. Output to the ventral horn Other outputs from the dorsal horn include those to the ventral horn. Many of them will be part of the anatomical basis of spinal reflex pathways. SUMMARY Recent advances in techniques, especially the intraneuronal injection of the enzyme horseradish peroxidase, have led to a new era in our understanding of spinal cord structure and function. Input to the cord is precisely organized: the primary afferent fibres from different types of receptors distribute their anatomically specific collaterals to particular parts of the dorsal horn, afferent fibres from the skin lay down a precise somatotopic map, input to the dorsal horn from descending systems is also distributed in a localized way. The neurones of the dorsal horn are varied in both structure and function, even so some quite specific cell types can be identified and the dendritic trees may respect laminar boundaries as determined cytoarchitectonically (although the majority of neurones have dendrites that

208 A. G. BROWN cut across these boundaries). The output pathways from the dorsal horn are many and various, but again they arise from cells in definite parts of the dorsal horn. The dorsal horn must be considered as a well-organized, and complex, part of the central nervous system. It cannot be considered as a structural or functional unit but is made up of many interacting parts that process input from the primary afferent fibres, from other levels of the spinal cord and from many descending pathways from the brain. REFERENCES ANDERSEN, P., ECCLES, J. C. & SEARS, T. A. (1964). Cortically evoked depolarization of primary afferent fibres in the spinal cord. Journal of Neurophysiology 27, 63-77. ANGAUT-PETIT, D. (1975). The dorsal column system. I. Existence of long ascending postsynaptic fibres in the cat's fascilus gracilis. Experimental Brain Research 22, 457-470. APPLEBAUM, A. E., BEALL, J. E., FOREMAN, R. D. & WILLIS, W. D. (1975). Organization and receptive fields of primate spinothalamic tract neurons. Journal of Neurophysiology 38, 572-586. ARMETT, C. J., GRAY, J. A. B. & PALMER, J. F. (1961). A group of neurones in the dorsal horn associated with cutaneous mechanoreceptors. Journal of Physiology 156, 611-622. BASBAUM, A. I., CLANTON, C. H. & FIELDS, H. L. (1976). Opiate and stimulus-produced analgesia: functional anatomy of a medullospinal pathway. Proceedings of the National Academy of Science, U.S.A. 73, 4685-4688. BASBAUM, A. I., CLANTON, C. H. & FIELDS, H. L. (1978). Three bulbospinal pathways from the rostral medulla of the cat: an autoradiographic stuy of pain modulating systems. Journal of Comparative Neurology 178, 209-224. BASBAUM, A. I. & FIELDS, H. L. (1977). The dorsolateral funiculus of the spinal cord: a major route for descending brainstem control. Neuroscience Abstracts 3, 499. BEALL, J. E., MARTIN, R. F., APPLEBAUM, A. E. & WILLIS, W. D. (1976). Inhibition of primate spinothalamic tract neurones by stimulation in the region of the nucleus raphe magnus. Brain Research 114, 328-333. BENNETT, G. J., ABDELMOUMENE, M., HAYASH, H. & DUBNER, R. (1980). Physiology and morphology of substantia gellatinosa neurones intracellularly stained with horseradish peroxidase. Journal of Comparative Neurology 194, 809-827. BROWN, A. G. (1973). Ascending and long spinal pathways: dorsal columns, spinocervical tract and spinothalamic tract. In Handbook of Sensory Physiology. II. The Somatosensory System, ed. IGo, A., pp. 315-338. Berlin, Heidelberg, New York: Springer-Verlag. BROWN, A. G. (1981). Organization in the Spinal Cord. Berlin, Heidelberg, New York: Springer Verlag. BROWN, A. G. (1982). The spinocervical tract. Progress in Neurobiology (in the Press). BROWN, A. G. & FyFiE, R. E. W. (1978). The morphology of Group Ia afferent fibre collaterals in the spinal cord of the cat. Journal of Physiology 274, 111-127. BROWN, A. G. & FYm, R. E. W. (1979). The morphology of Group lb afferent fibre collaterals in the spinal cord of the cat, Journal of Physiology 296, 215-228. BROWN, A. G., FYFFE, R. E. W. & NOBLE, R. (1980). Projections from Pacinian corpuscles and rapidly adapting mechanoreceptors of glabrous skin to the cat's spinal cord. Journal of Physiology 307, 385-400. BROWN, A. G., FYFFE, R. E. W., NOBLE, R., ROSE, P. K. & SNOW, P. J. (1980). The density, distribution and topographical organization of spinocervical tract neurones in the cat. Journal of Physiology 300, 409-428. BROWN, A. G. & FYFFE, R. E. W. (1981). Form and function of dorsal horn neurones with axons ascending the dorsal columns in the cat. Journal of Physiology 321, 31-48. BROWN, A. G., FYFFE, R. E. W., ROSE, P. K. & SNow, P. J. (1981). Spinal cord collaterals from axons of Type II slowly adapting units in the cat. Journal of Physiology 316, 469-480. BROWN, A. G. &RITHELYI, M. (eds.) (1981). Spinal Cord Sensation. Edinburgh: Scottish Academic Press. BROWN, A. G., ROSE, P. K. & SNOW, P. J. (1977). The morphology of hair follicle afferent fibre collaterals in the spinal cord of the cat. Journal of Physiology 272, 779-797. BROWN, A. G., ROSE, P. K. & SNow, P. J. (1978). Morphology and organization of axon collaterals from afferent fibres of slowly adapting Type I units in cat spinal cord. Journal of Physiology 277, 15-27.

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210 A. G. BROWN GOBEL, S. (1975). Golgi studies of the substantia gelatinosa neurons in the spinal trigeminal nucleus Journal of Comparative Neurology 162, 397-416. GOBEL, S. (1978 a). Golgi studies of the neurons in layer I of the dorsal horn of the medulla (Trigeminal Nucleus Caudalis). Journal of Comparative Neurology 180, 375-393. GOBEL, S. (1978b). Golgi studies of the neurons in layer II of the dorsal horn of the medulla (Trigeminal Nucleus Caudalis). Journal of Comparative Neurology 180, 395-413. GRAY, E. G. (1963). Electron microscopy of presynaptic organelles of the spinal cord. Journal of Anatomy 97, 101-106. GUILBAUD, G., OLIVERAS, J. L., GIESLER, G. & BESSON, J.-M. (1977). Effects induced by stimulation of the centralis inferior nucleus of the raphe on dorsal horn interneurons in cat's spinal cord. Brain Research 126, 355-360. Ht 3BARTH, K. E. & KERR, D. I. B. (1954). Central influences on spinal afferent conduction. Journal of Neurophysiology 17, 295-307. HOKFELT, T., KELLERTH, J.-O., NILSSON, G. & PERNOW, B. (1975). Experimental immunohistochemical studies on the localization and distribution of substance P in cat primary sensory neurons. Brain Research 100, 235-252. HOLMQVIST, B. & LUNDBERG, A. (1959). On the organization of the supraspinal inhibitory control of interneurones of various spinal reflex arcs. Archives italiennes de biologie 97, 340-356. HOLMQVIST, B. & LUNDBERG, A. (1961). Differential supraspinal control of synaptic actions evoked by volleys in the flexion reflex afferents in alpha motoneurones. Acta physiologica scandinavica 54, Supplement 186, 1-51. HOLMQVIST, B. LUNDBERG, A. & OSCARSSON, 0. (1960). Supraspinal inhibitory control of transmission to three ascending spinal paths influenced by the flexion reflex afferents. Archives italiennes de biologie 98, 60-80. HUBBARD, J. I. & OSCARSSON, 0. (1962). Localization of the cell bodies of the ventral spinocerebellar tract in lumbar segments of the cat. Journal of Comparative Neurology 118, 199-204. IGO, A. & RAMSEY, R. L. (1976). Thermosensory mechanisms in the spinal cord of monkeys. In Sensory Functions of the Skin in Primates, with Special Reference to Man, ed. ZOTTERMAN, Y., pp. 285-306. New York, Oxford: Pergamon Press. JANKOWSKA, E. & LINDSTROM, S. (1970). Morphological identification of physiologically defined neurons in the cat spinal cord. Brain Research 20, 323-326. JANKOWSKA, E. & LINDSTROM, S. (1972). Morphology of interneurones mediating Ia reciprocal inhibition of motoneurones in the spinal cord of the cat. Journal of Physiology 226, 805-823. KENSHALO, D. R., JR., LEONARD, R. B., CHUNG, J. M. & WILLIS, W. D. (1979). Responses of primate spinothalamic neurons to graded and repeated noxious heat stimuli. Journal of Neurophysiology 42, 1370-1389. KERR, F. W. L. (1966). The ultrastructure of the spinal tract of the trigeminal nerve and the substantia gelatinosa. Experimental Neurology 16, 359-376. KOLMODIN, G. M. (1957). Integrative processes in single spinal interneurones with proprioceptive connections. Acta physiologica scandinavica 40, suppl. 139, 1-89. KOLMODIN, G. M. & SKOGLUND C. R. (1960). Analysis of spinal interneurones activated by tactile and nociceptive stimulation. Acta physiologica scandinavica 50, 337-355. KUMAZAWA, T. & PERL, E. R. (1978). Excitation of marginal and substantia gelatinosa neurons in the primate spinal cord: indications of their place in dorsal horn organization. Journal of Comparative Neurology 177, 417-434. LAMOTTE, C. (1977). Distribution of the tract of Lissauer and the dorsal root fibers in the primate spinal cord. Journal of Comparative Neurology 172, 529-562. LIGHT, A. R. & PERL, E. R. (1979). Spinal termination of functionally identified primary afferent neurons with slowly conducting myelinated fibers. Journal of Comparative Neurology 186, 133-150. LIGHT, A. R., TREvINO, D. A. & PERL, E. R. (1979). Morphological features of functionally defined neurons in the marginal zone and substantia gelatinosa of the spinal dorsal horn. Journal of Comparative Neurology 186, 151-172. LLOYD, D. P. C. (1943). Reflex action in relation to pattern and peripheral source of afferent stimulation. Journal of Neurophysiology 6, 111-120. MATSUSHITA, M. (1969). Some aspects of the interneuronal connections in cat's spinal gray matter. Journal of Comparative Neurology 136, 57-80.

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