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Home , Dorsal column nuclei, Lemniscus (anatomy), Nociceptor, Somatosensory system

RESEARCH REVIEWS 55 (2007) 297– 313

available at www.sciencedirect.com

www.elsevier.com/locate/brainresrev

Review

The , with emphasis on structures important for

William D. Willis Jr.

Department of and Biology, University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77555-1069, USA

ARTICLE INFO ABSTRACT

Article history: Santiago Ramón y Cajal described a number of somatosensory structures, including several Accepted 20 May 2007 associated with pain, in his major work on the of the of Man and Available online 12 June 2007 . Our knowledge of such structures has been considerably expanded since Cajal because of the introduction of a number of experimental approaches that were not Keywords: available in his time. For example, Cajal made several drawings of peripheral TRP receptor , as well as of bare endings, but later work by others described Functional polarity additional somatosensory receptors and investigated the ultrastructure of bare nerve Lissauer's tract endings. Furthermore, the transducer molecules responsible for responses to nociceptive, Anterograde axonal transport thermal or chemical stimuli are now becoming known, including a series of TRP (transient Dorsal column-medial receptor potential) receptor molecules, such as TRPV1 (the receptor). Cajal pathway described the development of dorsal root and other sensory cells and related the disposition of their somata and neurites to his theory of the functional polarity of . He described the entry of both large and small afferent fibers into the , including the projections of their collaterals into different parts of the gray matter and into different tracts. He described a number of types of neurons in the gray matter, including ones in the marginal zone, substantia gelatinosa and head and neck of the dorsal horn. He found neurons in the deep dorsal horn whose extend dorsally into the superficial dorsal horn. Some of these neurons have since been shown by retrograde labeling to be cells. Cajal clearly described the dorsal column/ pathway, but the presence and course of the spinothalamic tract was unknown at the time. © 2007 Elsevier B.V. All rights reserved.

Contents

1. Introduction ...... 298 2. Sensory receptors of the somatosensory system ...... 299 3. Dorsal root ganglia ...... 303 4. Dorsal root entry zone and Lissauer's tract ...... 303 5. Dorsal horn neurons ...... 306

E-mail address: [email protected].

0165-0173/$ – see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.brainresrev.2007.05.010 298 BRAIN RESEARCH REVIEWS 55 (2007) 297– 313

6. Tracts ascending from the spinal cord to the brain...... 306 7. Summary and conclusions ...... 309 Acknowledgments ...... 311 References...... 311

1. Introduction neurons or their projections, immunohistochemistry, ultra- structural studies, electrophysiological recordings and beha- This review is based on a comparison of the description of vioral testing. This review will begin with the peripheral elements of the somatosensory system by Santiago Ramón y sensory receptors that detect somatosensory stimuli. Empha- Cajal that can be found in his major work on the Histology of the sis will then be placed on the spinal cord, where somatosen- Nervous System of Man and Vertebrates (Cajal, 1952, 1995 transla- sory information from the body is initially processed. Finally, tion) and current views. Many of Cajal's illustrations are of ascending pathways that signal this information to the brain preparations stained by the Golgi method. Cajal's observations will be introduced. Although it is the brain that provides the noted in this review are expanded upon by reference to later means for interpretation of such information in terms of work that has employed experimental approaches not avail- sensory (Mountcastle, 1998), this topic is beyond able to Cajal, such as retrograde and anterograde labeling of the scope of the present review and will not be discussed.

Fig. 1 – Panel I is a drawing by Cajal of a section of the of a . A Meissner corpuscle, E, is shown in a dermal papilla; it is supplied by a large myelinated , c. Osmic acid and hematoxylin stain. Panel II is a drawing of a in . It is also supplied by a large axon, a, that loses its sheath as it enters the capsule of the and then continues through much of the length of the inner core. Stained by the gold chloride method. (Panels I and II are from Cajal, 1952, 1995 translation.) Panel III shows a number of types of sensory receptors in the and . Meissner corpuscles are seen in several dermal papilli. Merkel disks are the endings of large myelinated in contact with Merkel cells found in the basal layer of the epidermis. Ruffini organs are present in the dermis and a Pacinian corpuscle in the deep dermis (or in subcutaneous ) (from Darian-Smith, 1984). BRAIN RESEARCH REVIEWS 55 (2007) 297– 313 299

oreceptors, such as Merkel disks and Ruffini organs (Fig. 1III; 2. Sensory receptors of the somatosensory reviewed in Darian-Smith, 1984; Willis and Coggeshall, 2004) system and has provided detail about the innervation of muscle, including the more complex muscle spindles found in higher Cajal (1952, 1995 translation) provides a description of some of vertebrates (Fig. 2III; see reviews by Barker, 1962; Matthews, the sensory receptor organs belonging to the somatosensory 1972; Willis and Coggeshall, 2004). system. Most of his emphasis is on the mechanoreceptors, Cajal also illustrated cutaneous free nerve endings that end presumably because of their large size and often elaborate in the dermis or that extend into the epidermis (Fig. 3I). “Free organization. For example, Cajal shows drawings of several nerve endings” of either finely myelinated axons (Aδ cutaneous types of mechanoreceptors, including a Meissner corpuscle or group III muscle and afferent fibers) or unmyelinated (Fig. 1I), a Pacinian corpuscle (Fig. 1II), a frog axons (C cutaneous or group IV muscle or joint afferent fibers) (Fig. 2I), and a (Fig. 2II). Later work by have been described much more fully by later investigators others has highlighted additional types of cutaneous mechan- (Perl, 1984; Mense, 1996). Heppelmann et al. (1990, 1995) showed

Fig. 2 – Panel I is a drawing by Cajal of a muscle spindle of the frog cutaneous pectoralis muscle stained by the Ehrlich method. Panel II is a drawing of a Golgi tendon organ from an adult cat and stained by the gold chloride method. The terminal arborization (a and c) of a large myelinated group Ib afferent fiber (b), and the attachment of the tendon to muscle fibers (e) are shown. (Panels I and II are from Cajal, 1952, 1995 translation). Panel III provides an overview of the innervation of mammalian . Groups Ia and II afferent fibers supply sensory endings in a muscle spindle, a group Ib fiber ends in a Golgi tendon organ, group III fibers terminate in paciniform corpuscles and free endings, and group IV fibers form free nerve endings. Alpha motor axons innervate motor end-plates on skeletal muscle fibers, and gamma motor axons supply motor endings on intrafusal muscle fibers. Vasomotor fibers innervate blood vessels (from Barker, 1962). 300 BRAIN RESEARCH REVIEWS 55 (2007) 297– 313

Fig. 3 – (I) Nerve endings in the epidermis of the paw skin in a kitten. Golgi method. The cornified epidermis is shown in panel A, the granular layer in panel B and the basal layer in panel C. Nerve fascicles in the dermis are seen in a, collaterals of these fibers in b, and terminals entering the epidermis in c and d (from Cajal, 1952, 1995 translation). (II) On the left are drawings of the “bare nerve endings” of two sensory receptors in the knee joint. One was a finely myelinated group III fiber and the other an unmyelinated group IV fiber. Terminal branches of these fibers are shown in the upper panels at the right. The axons have a series of swellings called “axonal beads”, and the axon terminals are imbedded in Schwann cells along most of their length. However, the lower panel on the right shows that the axon membrane is exposed to the extracellular space along regions called “bare areas.” The surface membranes of the bare areas of the axons are thought to contain receptor sites containing transducer molecules and associated channels (from Schaible and Schmidt, 1996). BRAIN RESEARCH REVIEWS 55 (2007) 297– 313 301 ultrastructural evidence that most of the surface membrane of physiological recordings from individual afferent axons dur- such endings (Fig. 3II) is actually covered by the processes of ing stimulation of their receptive fields have allowed afferent Schwann cells. Only in restricted regions is the terminal mem- fibers to be classified as mechanoreceptors, , brane freely exposed to the extracellular space. It was suggest- or (Perl, 1968; Bessou and Perl, 1969; Iggo and ed that such regions of membrane are likely to contain the Ogawa, 1971). The responses depend on the transducer me- receptors and channels that transduce sensory stimuli. chanism that is present in a particular sensory ending. Therefore, the term “free nerve ending” is an exaggeration. Nociceptors were defined by Sherrington (1906) as receptors The terminations of an Aδ mechanical in the that respond selectively to stimuli that cause damage or basal layer of the epidermis are illustrated in Fig. 4IA. Electro- threaten to cause damage. Some nociceptors selectively res-

Fig. 4 – (I) In panel A are shown the terminations of an Aδ mechanical nociceptor in the skin of a monkey (from Perl, 1984). Panels B–D are the responses of an Aδ mechanical nociceptor to several intensities of mechanical stimulation of the . The stimuli in panel B were applied by a blunt stimulator, whereas the in panel C was provided by a needle. The stimulus in panel D consisted of pinching of skin with serrated forceps. The dotted areas in panel E represent the receptive fields of 3 different Aδ mechanical nociceptors in different monkeys (from Perl, 1968). (II) The receptive fields of 4 different C polymodal nociceptors in human skin are shown in the drawing of a foot at the left. The responses of one of these C nociceptors were recorded from a peripheral nerve by microneurography. A diverse series of stimuli were applied during the times indicated by the thickenings of the baseline in panels (A–F). The stimuli used were: A, a pointed probe; B, firm stroke; C, squeezing the skin with forceps; D, needle prick; E, touching the skin with a glowing match; F, puncturing the skin with a hypodermic needle and then injecting KCl (from Torebjörk, 1974). 302 BRAIN RESEARCH REVIEWS 55 (2007) 297– 313 pond to particular kinds of noxious stimuli, such as noxious respond to noxious heat, lowered pH and certain pain- mechanical or noxious thermal stimuli. Other nociceptors, provoking chemicals, notably capsaicin and resiniferotoxin such as the polymodal nociceptors, are activated by various (Caterina and Julius, 2001). Other cutaneous nociceptors con- combinations of intense mechanical, thermal (heat and/or tain TRPV2 receptors, which are activated by high intensities of cold), and/or chemical stimuli (e.g., Bessou and Perl, 1969; noxious heat stimuli, but not by capsaicin or heat (Caterina et Torebjörk, 1974; see Willis and Coggeshall, 2004). al., 1999). Acid-sensing ion channels (ASICs) are activated by The responses of a mechanical nociceptor recorded in a lowered pH (Habelt et al., 2000; Immke and McCleskey, 2001; monkey are shown in Fig. 4IB–D(Perl, 1968), and the receptive Sutherland et al., 2001). Other transducer molecules, perhaps fields of 3 similar mechanical nociceptors are indicated in the belonging to the class of ENaC sodium channels (Price et al., drawings at the right in Fig. 4IE. The responses of a human C 2000; García-Añoveros et al., 2001), appear to be responsible for polymodal nociceptor to mechanical, thermal and chemical the responses of nociceptors to strong mechanical stimuli. stimuli (Torebjörk, 1974) are illustrated in Fig. 4II. The recep- Nociceptors can often be sensitized, with the consequence tive fields of several such receptors are shown on the drawing that they become much more responsive to noxious stimuli or of the foot at the left. The human recordings were done using even to normally innocuous stimuli (Bessou and Perl, 1969; see microneurography. review by Willis and Coggeshall, 2004). For example, Fig. 5B Although most mechanoreceptors are supplied by large or illustrates the enhancement of the responses of a C polymodal medium-sized myelinated fibers, some are associated with nociceptor that supplied monkey skin to graded heat stimuli finely myelinated axons (e.g., afferents from down hair fol- before and 10 min after a mild burn (LaMotte et al., 1983). A licles; Brown and Iggo, 1967; Burgess and Perl, 1967) or even parallel change in the human pain ratings associated with with unmyelinated axons (C mechanoreceptors; Iggo, 1960; comparable heat stimuli is shown in Fig. 5A. Another example Bessou et al., 1971). Conversely, although most nociceptors are would be the nociceptors that can be called “silent nocicep- associated with fine afferents, some have large myelinated tors.” These are normally unresponsive to mechanical stimuli, axons (Burgess and Perl, 1967; Djouhri and Lawson, 1999). but when sensitized, they become highly responsive to even Thermoreceptors have small myelinated or unmyelinated very weak mechanical stimuli (Schaible and Schmidt, 1985, axons (see Willis and Coggeshall, 2004). 1988; Handwerker et al., 1991; Meyer et al., 1991). Nociceptors are of particular interest because, when acti- Sensitization of nociceptors is often the result of exposure vated, they may evoke pain sensation. Morphological features of their terminals to irritant chemicals (such as capsaicin, are being found that allow the recognition of at least some formalin or oil), to inflammatory mediators (brady- types of nociceptors, and their electrophysiological responses kinin, prostaglandins and other products of arachidonic acid help account for their properties. For example, cutaneous metabolism, growth factors such as ), or a nociceptors often have TRPV1 receptors in their surface variety of neurotransmitters (excitatory amino acids, neuro- membranes. TRPV1 receptors are transducer molecules that kinins, , norepinephrine, histamine or other agents

Fig. 5 – The records in panel A show the pain ratings given by a human subject who was exposed to a graded series of noxious heat stimuli applied to an area of skin on the arm. The pain ratings provide an estimate of the time course of the pain experienced during each stimulus. The lower records were taken before the skin was mildly burned in the stimulated area, and the upper records show the enhanced pain responses to the same stimuli after the burn. In panel B, recordings were made from a C mechanoheat (CMH) nociceptor in a monkey subjected to the same series of heat stimuli. The responses were enhanced and the heat threshold lowered by the burn (from LaMotte et al., 1983). BRAIN RESEARCH REVIEWS 55 (2007) 297– 313 303

(ATP; nitric oxide, cytokines)) (see Kress and Reeh, 1996; Meyer Although Cajal admits the possibility under abnormal et al., 1996; Mizumura, 1997; Willis and Coggeshall, 2004). conditions of retrograde conduction in the axons of primary Sensitization of primary afferent nociceptors (also known sensory neurons, the discovery of dorsal root reflexes (which as “peripheral sensitization”) seems to depend in part on the are initiated at the synaptic terminals of primary afferents in activation of second messenger systems that cause the phos- the spinal cord and which then propagate antidromically out phorylation of transducer proteins, such as TRPV1, in the to the periphery) had to wait for many years (see review by surface membranes of the receptors (Kress and Guenther, Willis, 1999). 1999; Bhave and Gereau, 2004; Cortright and Szallasi, 2004; see review by Willis, 2006) or an increased expression of such transducer molecules (Carlton and Coggeshall, 2001). 4. Dorsal root entry zone and Lissauer's tract Like nociceptors, thermoreceptors are supplied by finely myelinated or unmyelinated afferent axons, and their res- Fig. 7I is a drawing by Cajal (1952; 1995 translation) of a ponses have now been suggested to result from the activation cross-section of the cervical spinal cord. The entry of large of their own special transducer proteins. Warm receptors afferents in the medial part of a dorsal root into the spinal contain several TRP receptors, TRPV3 and TRPV4, which are cord dorsal horn is indicated in B; these afferents are also activated by warming stimuli. Cold receptors contain TRPM8 shown to contribute to the cuneate fasciculus (C). The and/or ANKTM1 (also known as TRPA1), which, respectively, lateral course of the fine afferents into Lissauer's tract is respond to cooling (and menthol) and to cold (and to a variety seen in F. Terminals of the large afferents course into the of chemical substances) (Patapoutian et al., 2003; McKemy et neck of the dorsal horn (c) and into the ventral horn (h) al., 2002; Peier et al., 2002; Nealen et al., 2003; Bandell et al., whereas the fine afferents are destined for the substantia 2004). gelatinosa (a) and the head of the dorsal horn (b). More details concerning the large afferent projections are seen in Fig. 7II. Collaterals reaching the intermediate 3. Dorsal root ganglia are shown on the left in A and on the right in b; terminals in the head of the dorsal horn in panel C, and “deep” terminals in Cajal (1952; 1995 translation) illustrates the developmental the substantia gelatinosa in c. A “sensory-motor” bundle is changes that he observed in shown in a, as well as “arborizations in the motor nucleus” in cells as they progressed from a bipolar configuration to a B. The destination of fine afferents is seen more clearly in Fig. pseudounipolar one (Fig. 6I). He discusses his theory that 7III, where they pass from the dorsal root (A) laterally through activity in neurons normally passes in only one direction, the marginal plexus (B), while giving off collaterals (C), that from dendrites through the cell body to the axon (“axopetal” terminate in the substantia gelatinosa. functional polarity). Primary sensory neurons are the only The path followed by fine afferent fibers of the dorsal root neurons that have a direct connection with a sensory surface, into Lissauer's tract has been described by a number of invest- such as the skin. When these cells have a bipolar form during igators (Lissauer, 1885; Ranson and Billingsley, 1916; Sindou et development, the peripheral process conducts impulses al., 1974). However, Lissauer's tract includes not only primary toward the cell body, and the impulses are then conducted afferent fibers but also the axons of neurons intrinsic to the through the central process to the spinal cord. However, in dorsal horn (Coggeshall et al., 1981). the pseudounipolar dorsal root ganglion cells of adults, the Studies utilizing anterograde axonal transport of mar- nerve impulse can propagate from the peripheral process kers injected intracellularly into large myelinated afferent directly into the central process and thence to the spinal cord fibers indicate that the axons shown in Fig. 7II include (Fig. 6II). This confers an advantage in that the conduction group Ia and II fibers from muscle spindles that terminate time for sensory propagation is minimized. Fig. 6II shows in the intermediate region and motor nucleus and group Ib Cajal's diagram of this mode of propagation in an adult fibers from Golgi tendon organs that end in the inter- mammalian spinal ganglion sensory cell (D and C). However, mediate nucleus (Brown, 1981; Brown and Fyffe, 1978, 1979; Cajal also shows in this drawing a “fiber giving rise to a see Willis and Coggeshall, 2004). The axons that terminate pericellular arborization around the cell body of a ganglion in the neck of the dorsal horn would include a variety of cell” (Fig. 6IIE) that could evoke a discharge that passes along mechanoreceptors. Those that recurve dorsally from the the central process (Fig. 6IIC) to the spinal cord (Fig. 6IIM). neck of the dorsal horn to end more superficially are likely Cajal later states that “the cell body of spinal ganglion cells to be afferents (Brown et al., 1977). A difficulty also receives impulses delivered by autonomic fibers,” and he in much of Cajal's work is that he often used material from illustrates such a connection in his Fig. 169. Baskets of very young animals. This may have led to misinterpreta- sympathetic terminals have since been demonstrated in tion of what arrangements persist into adulthood. However, association with the cell bodies of dorsal root ganglion cells it has been shown in electrophysiological experiments that following peripheral nerve lesions (Fig. 6III; see McLachlan et neurons in lamina II can be activated either by noxious or al., 1993; Chung et al., 1996). Under such circumstances, it is innocuous mechanical stimuli (Kumazawa and Perl, 1976, possible for stimuli applied to the sympathetic nervous 1977, 1978). The recordings were from , since system to activate dorsal root ganglion cells (Devor et al., the cells could not be activated antidromically from rostral 1994). However, despite Cajal's assertion, it is unclear that levels of the spinal cord. The input from mechanoreceptors this arrangement occurs other than under pathological to neurons of the substantia gelatinosa may have been conditions. relayed through dorsal horn circuits or perhaps by fine 304 BRAIN RESEARCH REVIEWS 55 (2007) 297– 313

Fig. 6 – Panel I is a drawing by Cajal of a longitudinal section through a dorsal root ganglion from a chick embryo, stained by the reduced silver nitrate method. Unipolar dorsal root ganglion neurons are indicated by A and B. Forms transitional between uni- and bipolar neurons are indicated by C, D, F, and G. A bipolar is pointed out by E. Panel II shows the direction of nerve impulse propagation in a dorsal root ganglion neuron. A is the cell body of the neuron, B is the unipolar neurite, C the central process, and D the peripheral process. E is a nerve fiber forming a pericellular arborization around the ganglion cell ; this nerve fiber presumably originates from a sympathetic ganglion. The sensory receptor terminals at P are in the skin, and the central terminals at M are in the spinal cord. The arrows show the direction of propagation. (Panels I and II are from Cajal, 1952, 1995 translation.) Panel III illustrates a sympathetic pericellular arborization (stained for tyrosine hydroxylase) around a large dorsal root ganglion neuron in an animal with a (Chung et al., 1996).

terminal branches of mechanoreceptors not readily visua- show the distribution pattern of the terminals of two different lized at the light microscopic level. Aδ mechanical nociceptors in the dorsal horn, and Fig. 8C Light and Perl (1979) injected Aδ (group III) axons shows the endings of an axon that supplied a down hair intracellularly with an anterograde marker. Figs. 8A and B follicle receptor. BRAIN RESEARCH REVIEWS 55 (2007) 297– 313 305

Fig. 7 – Panel I is a drawing of a cross-section of the cervical spinal cord from a human. Among the structures indicated are: B, dorsal root; C, cuneate fasciculus; D, gracile fasciculus; F, tract of Lissauer; G, lateral corticospinal tract; H, dorsal ; a, substantia gelatinosa, b, head of dorsal horn; f, intermediate nucleus. (II) Cross-section of the spinal cord of a newborn rat, stained by the Golgi method. The projections of myelinated primary sensory axons to different regions of the gray matter are shown: A and b, intermediate nucleus; B, motor nucleus; C, head of dorsal horn; c, deep part of the substantia gelatinosa. (III) Cross-section of the spinal cord through the superficial dorsal horn and stained by the Golgi method. The projections of fine afferent fibers of the dorsal root, A, are shown in the marginal plexus, B, and as collaterals that terminate in the substantia gelatinosa in C (I–III from Cajal, 1952, 1995 translation).

Since it is very difficult to make intracellular impalements terminations of a cutaneous C polymodal nociceptor in of unmyelinated afferent fibers, Sugiura's group instead laminae I and II of the dorsal horn (Sugiura et al., 1986), injected an anterograde marker into individual cell bodies and Fig. 9II illustrates the more widespread distribution of of dorsal root ganglion cells in a small animal, the guinea pig. the terminals of a visceral C afferent fiber. Visceral afferent They were then able to follow the afferent fibers to their nociceptors were found to be distributed rostrocaudally over terminals in the dorsal horn. Fig. 9I shows the pattern of as many as six segments, in contrast to cutaneous no- 306 BRAIN RESEARCH REVIEWS 55 (2007) 297– 313

Fig. 8 – The axons of Aδ sensory neurons were injected intracellularly with horseradish peroxidase and later followed histologically to their terminals in the spinal cord. The axons were identified functionally before they were labeled. Panels A and B show the projections of 2 Aδ mechanical nociceptors and C those of a D hair follicle receptor. Panel A was in a monkey and B and C were in cats (from Light and Perl, 1979).

ciceptors, which had a more limited longitudinal distribution According to Gobel, the dendrites of stalked cells descend from (Sugiura et al., 1989). the cell body ventrally into deeper parts of lamina II and into lamina III and even IV. The axon has terminations in lamina I. The dendrites of islet cells are oriented longitudinally in 5. Dorsal horn neurons lamina II, and their axons project for a distance of up to 1 mm and end within lamina II. Also shown in Figs. 10IB and IIA are Cajal (1952, 1995 translation) was able to distinguish between a several “ neurons” (Schoenen, 1982) whose cell bodies number of different kinds of neurons in the spinal cord dorsal are in deep layers of the dorsal horn, but whose dendrites horn using the Golgi stain. In Fig. 10IA is his illustration of a ascend dorsally into lamina II and even into lamina I. large neuron in lamina I, the marginal zone. This type of cell is Retrogradely labeled neurons belonging to the spinothalamic often called a Waldeyer cell, after the person who described tract (Fig. 10III; Surmeier et al., 1988) and the postsynaptic such neurons in the spinal cord of the gorilla (Waldeyer, 1888). dorsal column pathway (Fig. 10IV; Brown and Fyffe, 1981) often Other, smaller neurons are also found in lamina I (Lima and have such dorsally projecting dendrites. Coimbra, 1988; Zhang and Craig, 1997; Zhang et al., 1996). Cajal also illustrated several types of neurons that he saw in the substantia gelatinosa, including “limiting” and “central” cells 6. Tracts ascending from the spinal cord to the (Figs. 10IIC and D). These were renamed “stalked” and “islet” brain cells, respectively, by Gobel (1978) in his investigation of the A number of tracts originate in the spinal cord and ascend to neurons of the spinal nucleus of the trigeminal, pars caudalis. the brain (see Willis and Coggeshall, 2004; Willis and BRAIN RESEARCH REVIEWS 55 (2007) 297– 313 307

Fig. 9 – Panel I shows the projection of a cutaneous C polymodal nociceptor into the spinal cord of a guinea pig. Phaseolus leukoagglutinin (PHA-L) was injected intracellularly into the soma of the dorsal root ganglion neuron that gave rise to the axon; the label was allowed to be transported centrally and then the axon was followed into the spinal cord histologically. The terminals were mostly in laminae I and II, as shown in panels A and B at different magnifications (from Sugiura et al., 1986). Panel II shows the projection of a visceral afferent C fiber into the spinal cord. The soma of the DRG neuron was injected with PHA-L, as in panel I, and followed histologically. The endings were in several laminae, and branches of the axon crossed to the contralateral side of the cord. The axon was distributed over 6 segments (from Sugiura et al., 1989).

Westlund, 1997, 2004). Some of these tracts are involved in tional-affective behaviors, including arousal and attention, as sensory functions, whereas others operate at a subconscious well as in somatic motor, autonomic and endocrine responses. level and often influence motor functions (e.g., the dorsal and Somatosensory discrimination appears to depend on the ventral spinocerebellar tracts). Several of the ascending tracts dorsal column-medial lemniscus system (including the post- that convey sensory information to the brain include the synaptic dorsal column pathway), the spinocervicothalamic spinoreticular, spinomesecephalic, and spinohypothalamic pathway, and the spinothalamic tract. Various types of pain tracts. These pathways are likely to participate in motiva- responses are triggered by activation not only of the 308 BRAIN RESEARCH REVIEWS 55 (2007) 297– 313

Fig. 10 – Panel I shows a drawing by Cajal (1952; 1995 translation) of several neurons in the dorsal horn of the spinal cord in a chick embryo stained by the Golgi method. A is a large, horizontally disposed neuron in the marginal zone that can be considered a “Waldeyer” cell of lamina I. B is another large neuron whose cell body is located in the head of the dorsal horn and whose widely dispersed dendrites include branches that extend dorsally into laminae I and II. The axons of both of these neurons, a and b, are shown to enter the lateral . Another neuron, C, is located in the interstitial nucleus of the lateral funiculus, presumably in what is now known as the lateral spinal nucleus. Its axon, c, follows a medially directed course. Panel II is a transverse section of the cervical spinal cord of a newborn kitten, stained using the Golgi method. A variety of types of neurons are depicted by Cajal. A is a large neuron whose cell body is in the deep layers of the dorsal horn. It has dendritic projections that extend dorsally into the substantia gelatinosa. Its axon, a, extends laterally in the direction of the lateral funiculus. Neurons of the substantia gelatinosa include a limiting cell, C and a central cell, D. The axon terminals indicated by F are collaterals of axons that first enter the deep dorsal horn and then recurve to end in the substantia gelatinosa. (Panels I and II are from Cajal, 1952; 1995 translation.) Panel III illustrates a spinothalamic tract neuron in the dorsal horn of a monkey. The neuron was injected intracellularly with horseradish peroxidase. Its dendrites ramify widely in the dorsal horn, and include branches that ascend into laminae I and II. The axon, arrow, crossed the midline near the level of the cell body. The responses of this neuron to graded intensities of mechanical stimuli are shown below the drawing of the foot; the drawing shows the receptive field in black. The spinothalamic neuron responded to tactile, as well as to noxious, mechanical stimuli. (Panel III is from Surmeier et al., 1988.) Panel IV is a reconstruction of a postsynaptic dorsal column neuron. The cell body was in lamina IIII, and the dendritic tree extended dorsally into lamina I. The axon (dashed line) passed medially to enter the dorsal column (from Brown and Fyffe, 1981). BRAIN RESEARCH REVIEWS 55 (2007) 297– 313 309 spinothalamic and spinoreticular tracts, but also of the postsynaptic dorsal column pathway, and the spinocervical, spinoparabrachial, and spinoamygdalar tracts. A surprising recent finding is that visceral depends more on the postsynaptic dorsal column pathway than on the spi- nothalamic tract (Fig. 12; Hirshberg et al., 1996; Al-Chaer et al., 1996a,b, 1998, 1999; Wang et al., 1999; Willis et al., 1999; Nauta et al., 2000; Houghton et al., 2001; Palecek et al., 2002), although the latter does convey information concerning painful visceral stimuli (Milne et al., 1981; Al-Chaer et al., 1999). Of especial interest is that midline myelotomies in that interrupt axons presumably belonging to this postsynaptic dorsal column system relieve the pain associated with pelvic cancer (Hirshberg et al., 1996; Nauta et al., 1997, 2000). Cajal had little to say about somatosensory pathways that ascend to the brain from the spinal cord. Most of these path- ways were discovered only after anterograde and retrograde tracing techniques became available. However, Cajal does illustrate the dorsal column-medial lemniscus pathway (and also the lateral corticospinal tract), as shown in Fig. 11. Cajal states that the “somatosensory pathway or medial lemniscus of Reil terminates entirely in the ventral nucleus [of the tha- lamus], and its freely ending terminal arborizations contact particular cells that give rise to the rostral or thalamocortical somatosensory pathway.” (This opinion was based on obser- vations on the of the mouse and the rabbit in Golgi preparations.) Neurons with short axons were found by Cajal “only in the somatosensory nucleus of the cat” (apparently not in that of mice). The recently described dorsal column visceral pain pathway is shown in Fig. 12. It appears that Cajal (1995 translation; see also Cajal, 1933) did not recognize the existence of a spinothalamic tract, although this pathway had been described in the late 1889s by Edinger (1889, 1890) and by Mott (1895). The likely role of the spinothalamic and associated tracts that ascend in the ante- rolateral white matter of the spinal cord in pain has been inferred from observations made by many clinical investiga- tors (e.g., Brown-Séquard, 1860; Foerster and Gagel, 1932; Head Fig. 11 – Diagram of the dorsal column-medial lemniscus and Thompson, 1906; Spiller, 1905; Spiller and Martin, 1912; pathway and of the lateral corticospinal tract to show the Gybels and Sweet, 1989). The discoveries of other pathways direction of action potential propagation in a sensory and a that may contribute to pain sensation were made at much motor pathway. A shows the lateral corticospinal tract after later times (for example, the spinocervicothalamic pathway by the axons leave pyramidal cells of the motor and as Morin (1955); the postsynaptic dorsal column pathway by they pass into the brain stem. The pathway decussates in the Uddenberg (1968); the spino-parabrachioamygdaloid pathway caudal medulla and then descends in the lateral funiculus, by Bernard and Besson (1990), and several spino-limbic giving off collaterals that on motor neurons, B, at pathways by Giesler and his colleagues, including the cervical, thoracic, and lumbosacral levels. C and D are sensory spinohypothalamic tract (Burstein and Giesler, 1989; Burstein neurons in dorsal root ganglia at upper thoracic and et al., 1987, 1990; Cliffer et al., 1991)). Details concerning these lumbosacral levels. They send collaterals rostrally, pathways are reviewed in Willis and Coggeshall (2004). respectively, in the cuneate and gracile fasciculi, and these synapse in the cuneate, E, and gracile, F, nuclei. Axons from the cross the midline and ascend in the 7. Summary and conclusions medial lemniscus, G, to the somatosensory , H. The thalamocortical projection to the somatosensory cortex, I, is In his major work on the Histology of the Nervous System of Man also shown (from Cajal, 1952, 1995 translation). and Vertebrates, Santiago Ramón y Cajal discusses a number of structures belonging to the somatosensory system, including structures since shown to be involved in responses to painful stimuli. However, later work has greatly expanded on the work Cajal describes some of the sensory receptors that signal of Cajal, in large part because of the introduction of a number information derived from stimuli applied to the body surface of experimental approaches that were not available to him. or to deep tissues, such as muscles. However, more recent 310 BRAIN RESEARCH REVIEWS 55 (2007) 297– 313

Fig. 12 – Representation of the dorsal column visceral pain pathway. A representative nociceptive visceral afferent from a pelvic visceral organ, the colon, is shown to enter the lumbosacral spinal cord over a dorsal root at L6-S1 and on postsynaptic dorsal column (PSDC) neurons. The PSDC neurons project rostrally in the midline dorsal column to synapse in the medial part of the nucleus gracilis. A comparable nociceptive visceral afferent fiber from the stomach projects to the thoracic spinal cord, where it synapses on PSDC neurons that project to the junction of the gracile (Gr) and cuneate (Cu) nuclei. These axons are at the boundary between the gracile and cuneate fasciculi. The neurons in the dorsal column nuclei that receive noxious visceral input then project contralaterally through the medial lemniscus to the ventral posterolateral nucleus of the thalamus (Th) (from Willis et al., 2004).

observations have led to the discovery of additional sense periments have shown that stimulation of sympathetic organs and to electrophysiological and behavioral studies that can activate some dorsal root ganglion neurons in neuropathic have helped to demonstrate the functional role of the various animals, presumably in part because of such connections. somatosensory receptors. However, it is unclear if such connections occur in the absence With respect to pain mechanisms, important findings of pathology. include the characterization of several types of nociceptors Large afferents are observed to enter the spinal cord (receptors that specifically respond to noxious stimuli), the through the medial part of the dorsal roots, whereas fine observation that these receptors contain transducer mole- afferent fibers enter through the lateral part and then enter cules, such as TRPV1 (the capsaicin receptor), TRPV2 and acid- Lissauer's tract. The large afferents project into the deep layers sensing ion channels (ASICs), which allow the nociceptors to of the dorsal horn and or into the ventral horn, whereas most respond to particular kinds of noxious stimuli. Another major fine afferents terminate in laminae I and II. These observa- advance is an analysis of the possible mechanisms by which tions have been enlarged upon in more recent studies in nociceptors can be sensitized and hence altered in such a way which an anterograde label has been injected intracellularly as to respond more vigorously to stimuli. Of particular note are into the axons, allowing identified primary afferent axons to the sensitizing actions of inflammatory mediators, such as be traced to their terminals. The afferents that have been bradykinin, prostaglandins and other chemical substances. traced in this fashion include Aβ and Aδ afferents from the Thermoreceptors have also been shown to contain trans- skin and groups Ia, Ib and II fibers from stretch receptors. The ducer molecules that allow them to detect warming or cooling projections of unmyelinated (C) afferent fibers have also been stimuli. These include TRPV3 and TRPV4, which are activated traced, but in a more indirect way. The anterograde label is by warming, and TRPM8 and ANKTM1, which are activated by injected into the identified cell bodies of dorsal root ganglion cooling or noxious cold (as well as by certain chemical cells, and then the label is traced into the spinal cord to the substances). terminals. It is desirable to do such experiments in a small Cajal relates the morphology of the cell bodies of primary animal, such as the guinea pig, so as to minimize the distance afferent neurons in the dorsal root ganglia to his theories of required for anterograde axonal transport of the label. functional polarity of neurons. He mentions his observation Cajal was able to demonstrate a number of different types that some dorsal root ganglion cells are contacted by of neurons in the dorsal horn, using the Golgi stain. These pericellular arborizations that appear to derive from post- included marginal neurons (Waldeyer cells), limiting and ganglionic sympathetic nerve fibers. Such arborizations have central cells of the substantia gelatinosa, and neurons of the since been described following peripheral nerve injuries. Ex- deep dorsal horn whose dendrites extend dorsally into the BRAIN RESEARCH REVIEWS 55 (2007) 297– 313 311 superficial dorsal horn. 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