BRAIN RESEARCH REVIEWS 55 (2007) 297– 313 available at www.sciencedirect.com www.elsevier.com/locate/brainresrev Review The somatosensory system, with emphasis on structures important 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 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 Histology of the Nervous System of Man and Available online 12 June 2007 Vertebrates. 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 mechanoreceptors, as well as of bare nerve 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 capsaicin receptor). Cajal lemniscus pathway described the development of dorsal root and other sensory ganglion cells and related the disposition 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, including the projections of their collaterals into different parts of the gray matter and into different white 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 dorsal horn. He found neurons in the deep dorsal horn whose dendrites extend dorsally into the superficial dorsal horn. Some of these neurons have since been shown by retrograde labeling to be spinothalamic tract cells. Cajal clearly described the dorsal column/medial lemniscus 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 perception (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 skin of a human finger. A Meissner corpuscle, E, is shown in a dermal papilla; it is supplied by a large myelinated axon, c. Osmic acid and hematoxylin stain. Panel II is a drawing of a Pacinian corpuscle in human skin. It is also supplied by a large axon, a, that loses its myelin sheath as it enters the capsule of the sense organ 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 epidermis and dermis. Meissner corpuscles are seen in several dermal papilli. Merkel disks are the endings of large myelinated axons 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 tissue) (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 joint afferent fibers) or unmyelinated (Fig. 1I), a Pacinian corpuscle (Fig. 1II), a frog muscle spindle axons (C cutaneous or group IV muscle or joint afferent fibers) (Fig. 2I), and a Golgi tendon organ (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 skeletal muscle. 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, thermoreceptors, brane freely exposed to the extracellular space. It was suggest- or nociceptors (Perl, 1968; Bessou and Perl, 1969; Iggo