the somatosensory system, with emphasis on structures ... · 2. sensory receptors of the...

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Review

The somatosensory system, with emphasis on structuresimportant for pain

William D. Willis Jr.Department of Neuroscience and Cell Biology, University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77555-1069, USA

A R T I C L E I N F O

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0165-0173/$ – see front matter © 2007 Elsevidoi:10.1016/j.brainresrev.2007.05.010

A B S T R A C T

Article history:Accepted 20 May 2007Available online 12 June 2007

Santiago Ramón y Cajal described a number of somatosensory structures, including severalassociated with pain, in his major work on the Histology of the Nervous System of Man andVertebrates. Our knowledge of such structures has been considerably expanded since Cajalbecause of the introduction of a number of experimental approaches that were notavailable in his time. For example, Cajal made several drawings of peripheralmechanoreceptors, as well as of bare nerve endings, but later work by others describedadditional somatosensory receptors and investigated the ultrastructure of bare nerveendings. Furthermore, the transducer molecules responsible for responses to nociceptive,thermal or chemical stimuli are now becoming known, including a series of TRP (transientreceptor potential) receptor molecules, such as TRPV1 (the capsaicin receptor). Cajaldescribed the development of dorsal root and other sensory ganglion cells and related thedisposition of their somata and neurites to his theory of the functional polarity of neurons.He described the entry of both large and small afferent fibers into the spinal cord, includingthe projections of their collaterals into different parts of the gray matter and into differentwhite matter 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 dorsalhorn. He found neurons in the deep dorsal horn whose dendrites extend dorsally into thesuperficial dorsal horn. Some of these neurons have since been shown by retrogradelabeling to be spinothalamic tract cells. Cajal clearly described the dorsal column/mediallemniscus pathway, but the presence and course of the spinothalamic tract was unknownat the time.

© 2007 Elsevier B.V. All rights reserved.

Keywords:TRP receptorFunctional polarityLissauer's tractAnterograde axonal transportDorsal column-mediallemniscus pathway

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2982. Sensory receptors of the somatosensory system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2993. Dorsal root ganglia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3034. Dorsal root entry zone and Lissauer's tract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3035. Dorsal horn neurons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 306

er B.V. All rights reserved.

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6. Tracts ascending from the spinal cord to the brain. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3067. Summary and conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 311References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 311

1. Introduction

This review is based on a comparison of the description ofelements of the somatosensory system by Santiago Ramón yCajal that can be found in hismajor work on theHistology of theNervous System of Man and Vertebrates (Cajal, 1952, 1995 transla-tion) and current views. Many of Cajal's illustrations are ofpreparations stained by the Golgimethod. Cajal's observationsnoted in this review are expanded upon by reference to laterwork that has employed experimental approaches not avail-able to Cajal, such as retrograde and anterograde labeling of

Fig. 1 – Panel I is a drawing by Cajal of a section of the skin of apapilla; it is supplied by a large myelinated axon, c. Osmic acid acorpuscle in human skin. It is also supplied by a large axon, a, thorgan and then continues throughmuch of the length of the innerfrom Cajal, 1952, 1995 translation.) Panel III shows a number ofMeissner corpuscles are seen in several dermal papilli. Merkel diMerkel cells found in the basal layer of the epidermis. Ruffini orgdeep dermis (or in subcutaneous tissue) (from Darian-Smith, 198

neurons or their projections, immunohistochemistry, ultra-structural studies, electrophysiological recordings and beha-vioral testing. This review will begin with the peripheralsensory receptors that detect somatosensory stimuli. Empha-sis will then be placed on the spinal cord, where somatosen-sory information from the body is initially processed. Finally,ascending pathways that signal this information to the brainwill be introduced. Although it is the brain that provides themeans for interpretation of such information in terms ofsensory perception (Mountcastle, 1998), this topic is beyondthe scope of the present review and will not be discussed.

human finger. A Meissner corpuscle, E, is shown in a dermalnd hematoxylin stain. Panel II is a drawing of a Pacinianat loses its myelin sheath as it enters the capsule of the sensecore. Stained by the gold chloridemethod. (Panels I and II are

types of sensory receptors in the epidermis and dermis.sks are the endings of large myelinated axons in contact withans are present in the dermis and a Pacinian corpuscle in the4).

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2. Sensory receptors of the somatosensorysystem

Cajal (1952, 1995 translation) provides a description of some ofthe sensory receptor organs belonging to the somatosensorysystem. Most of his emphasis is on the mechanoreceptors,presumably because of their large size and often elaborateorganization. For example, Cajal shows drawings of severaltypes of mechanoreceptors, including a Meissner corpuscle(Fig. 1I), a Pacinian corpuscle (Fig. 1II), a frog muscle spindle(Fig. 2I), and a Golgi tendon organ (Fig. 2II). Later work byothers has highlighted additional types of cutaneousmechan-

Fig. 2 – Panel I is a drawing by Cajal of a muscle spindle of the froPanel II is a drawing of a Golgi tendon organ from an adult cat anarborization (a and c) of a large myelinated group Ib afferent fibershown. (Panels I and II are from Cajal, 1952, 1995 translation). Panskeletal muscle. Groups Ia and II afferent fibers supply sensory etendon organ, group III fibers terminate in paciniform corpusclesAlpha motor axons innervate motor end-plates on skeletal muscintrafusal muscle fibers. Vasomotor fibers innervate blood vesse

oreceptors, such as Merkel disks and Ruffini organs (Fig. 1III;reviewed in Darian-Smith, 1984; Willis and Coggeshall, 2004)and has provided detail about the innervation of muscle,including the more complex muscle spindles found in highervertebrates (Fig. 2III; see reviews by Barker, 1962; Matthews,1972; Willis and Coggeshall, 2004).

Cajal also illustrated cutaneous free nerve endings that endin the dermis or that extend into the epidermis (Fig. 3I). “Freenerve endings” of either finelymyelinated axons (Aδ cutaneousor group III muscle and joint afferent fibers) or unmyelinatedaxons (C cutaneous or group IV muscle or joint afferent fibers)have been described much more fully by later investigators(Perl, 1984; Mense, 1996). Heppelmann et al. (1990, 1995) showed

g cutaneous pectoralis muscle stained by the Ehrlichmethod.d stained by the gold chloride method. The terminal(b), and the attachment of the tendon to muscle fibers (e) areel III provides an overview of the innervation of mammalianndings in a muscle spindle, a group Ib fiber ends in a Golgiand free endings, and group IV fibers form free nerve endings.le fibers, and gamma motor axons supply motor endings onls (from Barker, 1962).

Fig. 3 – (I) Nerve endings in the epidermis of the paw skin in a kitten. Golgi method. The cornified epidermis is shown in panelA, the granular layer in panel B and the basal layer in panel C. Nerve fascicles in the dermis are seen in a, collaterals of thesefibers in b, and terminals entering the epidermis in c and d (fromCajal, 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 anunmyelinated group IV fiber. Terminal branches of these fibers are shown in the upper panels at the right. The axons have aseries 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 axonmembrane is exposed to the extracellular space along regions called“bare areas.” The surfacemembranes of the bare areas of the axons are thought to contain receptor sites containing transducermolecules and associated channels (from Schaible and Schmidt, 1996).



ultrastructural evidence that most of the surface membrane ofsuch endings (Fig. 3II) is actually covered by the processes ofSchwann cells. Only in restricted regions is the terminal mem-brane freely exposed to the extracellular space. It was suggest-ed that such regions of membrane are likely to contain thereceptors and channels that transduce sensory stimuli.Therefore, the term “free nerve ending” is an exaggeration.

The terminations of an Aδ mechanical nociceptor in thebasal layer of the epidermis are illustrated in Fig. 4IA. Electro-

Fig. 4 – (I) In panel A are shown the terminations of an Aδ mechPanels B–D are the responses of an Aδ mechanical nociceptor tofield. The stimuli in panel B were applied by a blunt stimulator, wstimulus in panel D consisted of pinching of skin with serrated ffields of 3 different Aδ mechanical nociceptors in different monkpolymodal nociceptors in human skin are shown in the drawing owere recorded from a peripheral nerve by microneurography. Aindicated by the thickenings of the baseline in panels (A–F). TheC, squeezing the skin with forceps; D, needle prick; E, touching thypodermic needle and then injecting KCl (from Torebjörk, 1974

physiological recordings from individual afferent axons dur-ing stimulation of their receptive fields have allowed afferentfibers to be classified as mechanoreceptors, thermoreceptors,or nociceptors (Perl, 1968; Bessou and Perl, 1969; Iggo andOgawa, 1971). The responses depend on the transducer me-chanism that is present in a particular sensory ending.Nociceptors were defined by Sherrington (1906) as receptorsthat respond selectively to stimuli that cause damage orthreaten to cause damage. Some nociceptors selectively res-

anical nociceptor in the skin of a monkey (from Perl, 1984).several intensities of mechanical stimulation of the receptivehereas the stimulus in panel C was provided by a needle. Theorceps. The dotted areas in panel E represent the receptiveeys (from Perl, 1968). (II) The receptive fields of 4 different Cf a foot at the left. The responses of one of these C nociceptorsdiverse series of stimuli were applied during the timesstimuli used were: A, a pointed probe; B, firm stroke;he skin with a glowing match; F, puncturing the skin with a).


pond to particular kinds of noxious stimuli, such as noxiousmechanical or noxious thermal stimuli. Other nociceptors,such as the polymodal nociceptors, are activated by variouscombinations of intense mechanical, thermal (heat and/orcold), and/or chemical stimuli (e.g., Bessou and Perl, 1969;Torebjörk, 1974; see Willis and Coggeshall, 2004).

The responses of a mechanical nociceptor recorded in amonkey are shown in Fig. 4IB–D (Perl, 1968), and the receptivefields of 3 similar mechanical nociceptors are indicated in thedrawings at the right in Fig. 4IE. The responses of a human Cpolymodal nociceptor to mechanical, thermal and chemicalstimuli (Torebjörk, 1974) are illustrated in Fig. 4II. The recep-tive fields of several such receptors are shown on the drawingof the foot at the left. The human recordings were done usingmicroneurography.

Although most mechanoreceptors are supplied by large ormedium-sized myelinated fibers, some are associated withfinely myelinated axons (e.g., afferents from down hair fol-licles; Brown and Iggo, 1967; Burgess and Perl, 1967) or evenwith unmyelinated axons (C mechanoreceptors; Iggo, 1960;Bessou et al., 1971). Conversely, althoughmost nociceptors areassociated with fine afferents, some have large myelinatedaxons (Burgess and Perl, 1967; Djouhri and Lawson, 1999).Thermoreceptors have small myelinated or unmyelinatedaxons (see Willis and Coggeshall, 2004).

Nociceptors are of particular interest because, when acti-vated, they may evoke pain sensation. Morphological featuresare being found that allow the recognition of at least sometypes of nociceptors, and their electrophysiological responseshelp account for their properties. For example, cutaneousnociceptors often have TRPV1 receptors in their surfacemembranes. TRPV1 receptors are transducer molecules that

Fig. 5 – The records in panel A show the pain ratings given by a hheat stimuli applied to an area of skin on the arm. The pain ratinexperienced during each stimulus. The lower recordswere takenthe upper records show the enhanced pain responses to the samea Cmechanoheat (CMH) nociceptor in amonkey subjected to the sthe heat threshold lowered by the burn (from LaMotte et al., 198

respond to noxious heat, lowered pH and certain pain-provoking chemicals, notably capsaicin and resiniferotoxin(Caterina and Julius, 2001). Other cutaneous nociceptors con-tain TRPV2 receptors, which are activated by high intensities ofnoxious heat stimuli, but not by capsaicin or heat (Caterina etal., 1999). Acid-sensing ion channels (ASICs) are activated bylowered pH (Habelt et al., 2000; Immke and McCleskey, 2001;Sutherland et al., 2001). Other transducer molecules, perhapsbelonging to the class of ENaC sodium channels (Price et al.,2000; García-Añoveros et al., 2001), appear to be responsible forthe responses of nociceptors to strong mechanical stimuli.

Nociceptors can often be sensitized, with the consequencethat they becomemuchmore responsive to noxious stimuli oreven to normally innocuous stimuli (Bessou and Perl, 1969; seereview by Willis and Coggeshall, 2004). For example, Fig. 5Billustrates the enhancement of the responses of a C polymodalnociceptor that supplied monkey skin to graded heat stimulibefore and 10 min after a mild burn (LaMotte et al., 1983). Aparallel change in the human pain ratings associated withcomparable heat stimuli is shown in Fig. 5A. Another examplewould be the nociceptors that can be called “silent nocicep-tors.” These are normally unresponsive tomechanical stimuli,but when sensitized, they become highly responsive to evenvery weak mechanical stimuli (Schaible and Schmidt, 1985,1988; Handwerker et al., 1991; Meyer et al., 1991).

Sensitization of nociceptors is often the result of exposureof their terminals to irritant chemicals (such as capsaicin,formalin or mustard oil), to inflammatory mediators (brady-kinin, prostaglandins and other products of arachidonic acidmetabolism, growth factors such as nerve growth factor), or avariety of neurotransmitters (excitatory amino acids, neuro-kinins, serotonin, norepinephrine, histamine or other agents

uman subject whowas exposed to a graded series of noxiousgs provide an estimate of the time course of the painbefore the skinwasmildly burned in the stimulated area, andstimuli after the burn. In panel B, recordingsweremade fromame series of heat stimuli. The responseswere enhanced and3).


(ATP; nitric oxide, cytokines)) (see Kress and Reeh, 1996; Meyeret al., 1996; Mizumura, 1997; Willis and Coggeshall, 2004).

Sensitization of primary afferent nociceptors (also knownas “peripheral sensitization”) seems to depend in part on theactivation of second messenger systems that cause the phos-phorylation of transducer proteins, such as TRPV1, in thesurface membranes of the receptors (Kress and Guenther,1999; Bhave and Gereau, 2004; Cortright and Szallasi, 2004; seereview by Willis, 2006) or an increased expression of suchtransducer molecules (Carlton and Coggeshall, 2001).

Like nociceptors, thermoreceptors are supplied by finelymyelinated or unmyelinated afferent axons, and their res-ponses have now been suggested to result from the activationof their own special transducer proteins. Warm receptorscontain several TRP receptors, TRPV3 and TRPV4, which areactivated by warming stimuli. Cold receptors contain TRPM8and/or ANKTM1 (also known as TRPA1), which, respectively,respond to cooling (and menthol) and to cold (and to a varietyof chemical substances) (Patapoutian et al., 2003; McKemy etal., 2002; Peier et al., 2002; Nealen et al., 2003; Bandell et al.,2004).

3. Dorsal root ganglia

Cajal (1952; 1995 translation) illustrates the developmentalchanges that he observed in vertebrate dorsal root ganglioncells as they progressed from a bipolar configuration to apseudounipolar one (Fig. 6I). He discusses his theory thatactivity in neurons normally passes in only one direction,from dendrites through the cell body to the axon (“axopetal”functional polarity). Primary sensory neurons are the onlyneurons that have a direct connection with a sensory surface,such as the skin. When these cells have a bipolar form duringdevelopment, the peripheral process conducts impulsestoward the cell body, and the impulses are then conductedthrough the central process to the spinal cord. However, inthe pseudounipolar dorsal root ganglion cells of adults, thenerve impulse can propagate from the peripheral processdirectly into the central process and thence to the spinal cord(Fig. 6II). This confers an advantage in that the conductiontime for sensory propagation is minimized. Fig. 6II showsCajal's diagram of this mode of propagation in an adultmammalian spinal ganglion sensory cell (D and C). However,Cajal also shows in this drawing a “fiber giving rise to apericellular arborization around the cell body of a ganglioncell” (Fig. 6IIE) that could evoke a discharge that passes alongthe central process (Fig. 6IIC) to the spinal cord (Fig. 6IIM).Cajal later states that “the cell body of spinal ganglion cellsalso receives impulses delivered by autonomic fibers,” and heillustrates such a connection in his Fig. 169. Baskets ofsympathetic terminals have since been demonstrated inassociation with the cell bodies of dorsal root ganglion cellsfollowing peripheral nerve lesions (Fig. 6III; see McLachlan etal., 1993; Chung et al., 1996). Under such circumstances, it ispossible for stimuli applied to the sympathetic nervoussystem to activate dorsal root ganglion cells (Devor et al.,1994). However, despite Cajal's assertion, it is unclear thatthis arrangement occurs other than under pathologicalconditions.

Although Cajal admits the possibility under abnormalconditions of retrograde conduction in the axons of primarysensory neurons, the discovery of dorsal root reflexes (whichare initiated at the synaptic terminals of primary afferents inthe spinal cord and which then propagate antidromically outto the periphery) had to wait for many years (see review byWillis, 1999).

4. Dorsal root entry zone and Lissauer's tract

Fig. 7I is a drawing by Cajal (1952; 1995 translation) of across-section of the cervical spinal cord. The entry of largeafferents in the medial part of a dorsal root into the spinalcord dorsal horn is indicated in B; these afferents are alsoshown to contribute to the cuneate fasciculus (C). Thelateral course of the fine afferents into Lissauer's tract isseen in F. Terminals of the large afferents course into theneck of the dorsal horn (c) and into the ventral horn (h)whereas the fine afferents are destined for the substantiagelatinosa (a) and the head of the dorsal horn (b).

More details concerning the large afferent projections areseen in Fig. 7II. Collaterals reaching the intermediate nucleusare shown on the left in A and on the right in b; terminals inthe head of the dorsal horn in panel C, and “deep” terminals inthe substantia gelatinosa in c. A “sensory-motor” bundle isshown in a, as well as “arborizations in the motor nucleus” inB. The destination of fine afferents is seen more clearly in Fig.7III, where they pass from the dorsal root (A) laterally throughthe marginal plexus (B), while giving off collaterals (C), thatterminate in the substantia gelatinosa.

The path followed by fine afferent fibers of the dorsal rootinto Lissauer's tract has been described by a number of invest-igators (Lissauer, 1885; Ranson and Billingsley, 1916; Sindou etal., 1974). However, Lissauer's tract includes not only primaryafferent fibers but also the axons of neurons intrinsic to thedorsal horn (Coggeshall et al., 1981).

Studies utilizing anterograde axonal transport of mar-kers injected intracellularly into large myelinated afferentfibers indicate that the axons shown in Fig. 7II includegroup Ia and II fibers from muscle spindles that terminatein the intermediate region and motor nucleus and group Ibfibers from Golgi tendon organs that end in the inter-mediate nucleus (Brown, 1981; Brown and Fyffe, 1978, 1979;see Willis and Coggeshall, 2004). The axons that terminatein the neck of the dorsal horn would include a variety ofmechanoreceptors. Those that recurve dorsally from theneck of the dorsal horn to end more superficially are likelyto be hair follicle afferents (Brown et al., 1977). A difficultyin much of Cajal's work is that he often used material fromvery young animals. This may have led to misinterpreta-tion of what arrangements persist into adulthood. However,it has been shown in electrophysiological experiments thatneurons in lamina II can be activated either by noxious orinnocuous mechanical stimuli (Kumazawa and Perl, 1976,1977, 1978). The recordings were from interneurons, sincethe cells could not be activated antidromically from rostrallevels of the spinal cord. The input from mechanoreceptorsto neurons of the substantia gelatinosa may have beenrelayed through dorsal horn circuits or perhaps by fine

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


terminal branches of mechanoreceptors not readily visua-lized at the light microscopic level.

Light and Perl (1979) injected Aδ (group III) axonsintracellularly with an anterograde marker. Figs. 8A and B

show the distribution pattern of the terminals of two differentAδ mechanical nociceptors in the dorsal horn, and Fig. 8Cshows the endings of an axon that supplied a down hairfollicle receptor.

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, dorsalspinocerebellar tract; a, substantia gelatinosa, b, head of dorsal horn; f, intermediate nucleus. (II) Cross-section of the spinalcord of a newborn rat, stained by the Golgimethod. The projections ofmyelinated primary sensory axons to different regions ofthe gray matter are shown: A and b, intermediate nucleus; B, motor nucleus; C, head of dorsal horn; c, deep part of thesubstantia 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 themarginal plexus, B, and as collaterals that terminatein the substantia gelatinosa in C (I–III from Cajal, 1952, 1995 translation).


Since it is very difficult to make intracellular impalementsof unmyelinated afferent fibers, Sugiura's group insteadinjected an anterograde marker into individual cell bodiesof dorsal root ganglion cells in a small animal, the guinea pig.They were then able to follow the afferent fibers to theirterminals in the dorsal horn. Fig. 9I shows the pattern of

terminations of a cutaneous C polymodal nociceptor inlaminae I and II of the dorsal horn (Sugiura et al., 1986),and Fig. 9II illustrates the more widespread distribution ofthe terminals of a visceral C afferent fiber. Visceral afferentnociceptors were found to be distributed rostrocaudally overas many as six segments, in contrast to cutaneous no-

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


ciceptors, which had a more limited longitudinal distribution(Sugiura et al., 1989).

5. Dorsal horn neurons

Cajal (1952, 1995 translation) was able to distinguish between anumber of different kinds of neurons in the spinal cord dorsalhorn using the Golgi stain. In Fig. 10IA is his illustration of alarge neuron in lamina I, themarginal zone. This type of cell isoften called a Waldeyer cell, after the person who describedsuch neurons in the spinal cord of the gorilla (Waldeyer, 1888).Other, smaller neurons are also found in lamina I (Lima andCoimbra, 1988; Zhang and Craig, 1997; Zhang et al., 1996). Cajalalso illustrated several types of neurons that he saw in thesubstantia gelatinosa, including “limiting” and “central” cells(Figs. 10IIC and D). These were renamed “stalked” and “islet”cells, respectively, by Gobel (1978) in his investigation of theneurons of the spinal nucleus of the trigeminal, pars caudalis.

According to Gobel, the dendrites of stalked cells descend fromthe cell body ventrally into deeper parts of lamina II and intolamina III and even IV. The axon has terminations in lamina I.The dendrites of islet cells are oriented longitudinally inlamina II, and their axons project for a distance of up to 1 mmand end within lamina II. Also shown in Figs. 10IB and IIA areseveral “antenna neurons” (Schoenen, 1982) whose cell bodiesare in deep layers of the dorsal horn, but whose dendritesascend dorsally into lamina II and even into lamina I.Retrogradely labeled neurons belonging to the spinothalamictract (Fig. 10III; Surmeier et al., 1988) and the postsynapticdorsal columnpathway (Fig. 10IV; Brown and Fyffe, 1981) oftenhave such dorsally projecting dendrites.

6. Tracts ascending from the spinal cord to thebrain

A number of tracts originate in the spinal cord and ascend tothe brain (see Willis and Coggeshall, 2004; Willis and

Fig. 9 – Panel I shows the projection of a cutaneous C polymodal nociceptor into the spinal cord of a guinea pig. Phaseolusleukoagglutinin (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. Theterminals 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 withPHA-L, as in panel I, and followed histologically. The endings were in several laminae, and branches of the axon crossed to thecontralateral 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 insensory functions, whereas others operate at a subconsciouslevel and often influence motor functions (e.g., the dorsal andventral spinocerebellar tracts). Several of the ascending tractsthat convey sensory information to the brain include thespinoreticular, spinomesecephalic, and spinohypothalamictracts. These pathways are likely to participate in motiva-

tional-affective behaviors, including arousal and attention, aswell as in somaticmotor, autonomic and endocrine responses.Somatosensory discrimination appears to depend on thedorsal column-medial lemniscus system (including the post-synaptic dorsal column pathway), the spinocervicothalamicpathway, and the spinothalamic tract. Various types of painresponses are triggered by activation not only of the

Fig. 10 – Panel I shows a drawing by Cajal (1952; 1995 translation) of several neurons in the dorsal horn of the spinal cord in achick embryo stained by the Golgi method. A is a large, horizontally disposed neuron in the marginal zone that can beconsidered a “Waldeyer” cell of lamina I. B is another large neuronwhose cell body is located in the head of the dorsal horn andwhose widely dispersed dendrites include branches that extend dorsally into laminae I and II. The axons of both of theseneurons, a and b, are shown to enter the lateral funiculus. Another neuron, C, is located in the interstitial nucleus of the lateralfuniculus, presumably in what is now known as the lateral spinal nucleus. Its axon, c, follows amedially directed course. PanelII is a transverse section of the cervical spinal cord of a newborn kitten, stained using the Golgi method. A variety of types ofneurons are depicted by Cajal. A is a large neuron whose cell body is in the deep layers of the dorsal horn. It has dendriticprojections that extend dorsally into the substantia gelatinosa. Its axon, a, extends laterally in the direction of the lateralfuniculus. Neurons of the substantia gelatinosa include a limiting cell, C and a central cell, D. The axon terminals indicated by Fare collaterals of axons that first enter the deep dorsal horn and then recurve to end in the substantia gelatinosa. (Panels I and IIare from Cajal, 1952; 1995 translation.) Panel III illustrates a spinothalamic tract neuron in the dorsal horn of a monkey. Theneuron was injected intracellularly with horseradish peroxidase. Its dendrites ramify widely in the dorsal horn, and includebranches that ascend into laminae I and II. The axon, arrow, crossed themidline near the level of the cell body. The responses ofthis neuron to graded intensities of mechanical stimuli are shown below the drawing of the foot; the drawing shows thereceptive field in black. The spinothalamic neuron responded to tactile, as well as to noxious, mechanical stimuli. (Panel III isfrom Surmeier et al., 1988.) Panel IV is a reconstruction of a postsynaptic dorsal columnneuron. The cell bodywas in lamina IIII,and the dendritic tree extended dorsally into lamina I. The axon (dashed line) passedmedially to enter the dorsal column (fromBrown and Fyffe, 1981).


Fig. 11 – Diagram of the dorsal column-medial lemniscuspathway and of the lateral corticospinal tract to show thedirection of action potential propagation in a sensory and amotor pathway. A shows the lateral corticospinal tract afterthe axons leave pyramidal cells of the motor cortex and asthey pass into the brain stem. The pathway decussates in thecaudal medulla and then descends in the lateral funiculus,giving off collaterals that synapse on motor neurons, B, atcervical, thoracic, and lumbosacral levels. C and D are sensoryneurons in dorsal root ganglia at upper thoracic andlumbosacral levels. They send collaterals rostrally,respectively, in the cuneate and gracile fasciculi, and these


spinothalamic and spinoreticular tracts, but also of thepostsynaptic dorsal column pathway, and the spinocervical,spinoparabrachial, and spinoamygdalar tracts. A surprisingrecent finding is that visceral nociception depends more onthe 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; Nautaet al., 2000; Houghton et al., 2001; Palecek et al., 2002), althoughthe latter does convey information concerning painful visceralstimuli (Milne et al., 1981; Al-Chaer et al., 1999). Of especialinterest is that midlinemyelotomies in humans that interruptaxons presumably belonging to this postsynaptic dorsalcolumn visceral pain system relieve the pain associated withpelvic cancer (Hirshberg et al., 1996; Nauta et al., 1997, 2000).

Cajal had little to say about somatosensory pathways thatascend to the brain from the spinal cord. Most of these path-ways were discovered only after anterograde and retrogradetracing techniques became available. However, Cajal doesillustrate the dorsal column-medial lemniscus pathway (andalso the lateral corticospinal tract), as shown in Fig. 11. Cajalstates that the “somatosensory pathway or medial lemniscusof Reil terminates entirely in the ventral nucleus [of the tha-lamus], and its freely ending terminal arborizations contactparticular cells that give rise to the rostral or thalamocorticalsomatosensory pathway.” (This opinion was based on obser-vations on the brains of the mouse and the rabbit in Golgipreparations.) Neurons with short axons were found by Cajal“only in the somatosensory nucleus of the cat” (apparently notin that of mice). The recently described dorsal column visceralpain 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 byEdinger (1889, 1890) and by Mott (1895). The likely role of thespinothalamic and associated tracts that ascend in the ante-rolateral white matter of the spinal cord in pain has beeninferred from observations made by many clinical investiga-tors (e.g., Brown-Séquard, 1860; Foerster and Gagel, 1932; Headand Thompson, 1906; Spiller, 1905; Spiller and Martin, 1912;Gybels and Sweet, 1989). The discoveries of other pathwaysthat may contribute to pain sensation were made at muchlater times (for example, the spinocervicothalamic pathway byMorin (1955); the postsynaptic dorsal column pathway byUddenberg (1968); the spino-parabrachioamygdaloid pathwayby Bernard and Besson (1990), and several spino-limbicpathways by Giesler and his colleagues, including thespinohypothalamic tract (Burstein and Giesler, 1989; Bursteinet al., 1987, 1990; Cliffer et al., 1991)). Details concerning thesepathways are reviewed in Willis and Coggeshall (2004).

synapse in the cuneate, E, and gracile, F, nuclei. Axons fromthe dorsal column nuclei cross the midline and ascend in themedial lemniscus, G, to the somatosensory thalamus, H. Thethalamocortical projection to the somatosensory cortex, I, isalso shown (from Cajal, 1952, 1995 translation).

7. Summary and conclusions

In his major work on the Histology of the Nervous System of Manand Vertebrates, Santiago Ramón y Cajal discusses a number ofstructures belonging to the somatosensory system, includingstructures since shown to be involved in responses to painfulstimuli. However, laterwork has greatly expanded on theworkof Cajal, in large part because of the introduction of a numberof experimental approaches that were not available to him.

Cajal describes some of the sensory receptors that signalinformation derived from stimuli applied to the body surfaceor to deep tissues, such as muscles. However, more recent

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


observations have led to the discovery of additional senseorgans and to electrophysiological and behavioral studies thathave helped to demonstrate the functional role of the varioussomatosensory receptors.

With respect to pain mechanisms, important findingsinclude the characterization of several types of nociceptors(receptors that specifically respond to noxious stimuli), theobservation that these receptors contain transducer mole-cules, such as TRPV1 (the capsaicin receptor), TRPV2 and acid-sensing ion channels (ASICs), which allow the nociceptors torespond to particular kinds of noxious stimuli. Another majoradvance is an analysis of the possible mechanisms by whichnociceptors can be sensitized and hence altered in such a wayas to respondmore vigorously to stimuli. Of particular note arethe sensitizing actions of inflammatory mediators, such asbradykinin, prostaglandins and other chemical substances.

Thermoreceptors have also been shown to contain trans-ducer molecules that allow them to detect warming or coolingstimuli. These include TRPV3 and TRPV4, which are activatedby warming, and TRPM8 and ANKTM1, which are activated bycooling or noxious cold (as well as by certain chemicalsubstances).

Cajal relates the morphology of the cell bodies of primaryafferent neurons in the dorsal root ganglia to his theories offunctional polarity of neurons. He mentions his observationthat some dorsal root ganglion cells are contacted bypericellular arborizations that appear to derive from post-ganglionic sympathetic nerve fibers. Such arborizations havesince been described following peripheral nerve injuries. Ex-

periments have shown that stimulation of sympathetic nervescan activate some dorsal root ganglion neurons in neuropathicanimals, presumably in part because of such connections.However, it is unclear if such connections occur in the absenceof pathology.

Large afferents are observed to enter the spinal cordthrough the medial part of the dorsal roots, whereas fineafferent fibers enter through the lateral part and then enterLissauer's tract. The large afferents project into the deep layersof the dorsal horn and or into the ventral horn, whereas mostfine afferents terminate in laminae I and II. These observa-tions have been enlarged upon in more recent studies inwhich an anterograde label has been injected intracellularlyinto the axons, allowing identified primary afferent axons tobe traced to their terminals. The afferents that have beentraced in this fashion include Aβ and Aδ afferents from theskin and groups Ia, Ib and II fibers from stretch receptors. Theprojections of unmyelinated (C) afferent fibers have also beentraced, but in a more indirect way. The anterograde label isinjected into the identified cell bodies of dorsal root ganglioncells, and then the label is traced into the spinal cord to theterminals. It is desirable to do such experiments in a smallanimal, such as the guinea pig, so as to minimize the distancerequired for anterograde axonal transport of the label.

Cajal was able to demonstrate a number of different typesof neurons in the dorsal horn, using the Golgi stain. Theseincluded marginal neurons (Waldeyer cells), limiting andcentral cells of the substantia gelatinosa, and neurons of thedeep dorsal horn whose dendrites extend dorsally into the


superficial dorsal horn. Some of the latter neurons have sincebeen shown to be spinothalamic or postsynaptic dorsalcolumn neurons.

Cajal provides an accurate picture of the course of thedorsal column-medial lemniscus pathway in the spinal cord,through the brain stem and to its termination in the thalamus.Work by others has led to a description of the spinothalamictract and of other pathways that convey somatosensoryinformation (including pain) to the brain.

Acknowledgments

The author thanks Griselda Gonzales and Kelli Gondesen fortheir expert technical assistance.

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the somatosensory system, with emphasis on structures ... · 2. sensory receptors of the...

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