ANATOMY AND PHYSIOLOGY OF PAIN

Historical Perspective
For more than a century, views on the nature of pain sensation have been dominated by two major theories. One, known as the specificity theory, was from the beginning associated with the name of von Frey. He asserted that the skin consisted of a mosaic of discrete sensory spots and that each spot, when stimulated, gave rise to one sensation—either pain, pressure, warmth, or cold; in his view, each of these sensations had a distinctive end organ in the skin and each stimulus-specific end organ was connected by its own private pathway to the brain. A second theory was that of Goldscheider, who abandoned his own earlier discovery of pain spots to argue that they simply represented pressure spots, a sufficiently intense stimulation of which could produce pain. According to the latter theory, there were no distinctive pain receptors, and the sensation of pain was the result of the summation of impulses excited by pressure or thermal stimuli applied to the skin. Originally called the intensivity theory, it later became known as the pattern or summation theory.
In an effort to conciliate the pattern and specificity theories, Head and his colleagues, in 1905, formulated a novel concept of pain sensation, based on observations that followed division of the cutaneous branch of the radial nerve in Head's own forearm. The zone of impaired sensation contained an innermost area in which superficial sensation was completely abolished. This was surrounded by a narrower (“intermediate”) zone, in which pain sensation was preserved but poorly localized; extreme degrees of temperature were recognized in the intermediate zone, but perception of touch, lesser differences of temperature, and two-point discrimination were abolished. To explain these findings, Head postulated the existence of two systems of cutaneous receptors and conducting fibers: (1) an ancient protopathic system, subserving pain and extreme differences in temperature and yielding ungraded, diffuse impressions of an all-or-none type, and (2) a more recently evolved epicritic system, which mediated touch, two-point discrimination, and lesser differences in temperature as well as localized pain. The pain and hyperesthesia that follow damage to a peripheral nerve were attributed to a loss of inhibition that was normally exerted by the epicritic upon the protopathic system. This theory was used for many years to explain the sensory alterations that occur with both peripheral and central (thalamic) lesions. It lost credibility for several reasons, but mainly because Head's original observations (and deductions upon which they were based) could not be corroborated (see Trotter and Davies; also Walshe). Nevertheless, both a fast and a slow form of pain conduction were later corroborated (see below).
A much later refinement of the pattern and specificity concepts of pain was made in 1965, when Melzack and Wall propounded their “gate-control” theory. They observed, in decerebrate and spinal cats, that peripheral stimulation of large myelinated fibers produced a negative dorsal root potential and that stimulation of small C (pain) fibers caused a positive dorsal root potential. They postulated that these potentials, which were a reflection of presynaptic inhibition or excitation, modulated the activity of secondary transmitting neurons (T cells) in the dorsal horn, and that this modulation was mediated through inhibitory (I) cells. The essence of this theory is that the large-diameter fibers excite the I cells, which, in turn, cause a presynaptic inhibition of the T cells; conversely, the small pain afferents inhibit the I cells, leaving the T cells in an excitatory state. Melzack and Wall emphasized that pain impulses from the dorsal horn must also be under the control of a descending system of fibers from the brainstem, thalamus, and limbic lobes.
At first the gate-control mechanisms seemed to offer an explanation of the pain of ruptured disc and of certain chronic neuropathies (large fiber outfall), and attempts were made to relieve pain by subjecting the peripheral nerves and dorsal columns (presumably their large myelinated fibers) to sustained, transcutaneous electrical stimulation. Such selective stimulation would theoretically “close” the gate. In some clinical situations, these procedures have indeed given relief from pain, but not necessarily due to stimulation of large myelinated fibers alone (see Taub and Campbell). And in a number of other instances relating to pain in large- and small-fiber neuropathies, the clinical behavior has been quite out of keeping with what one would expect on the basis of the gate-control mechanism. As with preceding pain theories, flaws have been exposed in the physiologic observations on which the theory is based. These and other aspects of the gate-control theory of pain have been critically reviewed by P. W. Nathan.
During the last few decades there has been a significant accrual of information on cutaneous sensibility, demanding a modification of earlier anatomic-physiologic and clinical concepts. Interestingly, much of this information is still best described and rationalized in the general framework of specificity, as will be evident from the ensuing discussion on pain and that on other forms of cutaneous sensibility in the chapter that follows.
Pain Receptors and Peripheral Afferent Pathways
In terms of peripheral pain mechanisms, as already implied, there is indeed a high degree of specificity, though not an absolute specificity in the von Frey sense. It is now well established that two types of afferent fibers in the distal axons of primary sensory neurons respond maximally to nociceptive (i.e., potentially tissue-damaging) stimuli. One type is the very fine, unmyelinated, slowly conducting C fiber (0.4 to 1.1 mm in diameter), and the other is the thinly myelinated, more rapidly conducting A-delta (A-d) fiber (1.0 to 5.0 mm in diameter). The peripheral terminations of both these primary pain afferents, or receptors, are the free, profusely branched nerve endings in the skin and other organs; these are covered by Schwann cells and contain little or no myelin. There is considerable evidence, based on their response characteristics, that a degree of subspecialization exists within these freely branching, nonencapsulated endings and their small fiber afferents. Three broad categories of free endings, or receptors, are recognized: mechanoreceptors, thermoreceptors, and polymodal nociceptors. Each ending transduces stimulus energy into an action potential in nerve membranes. The first two types of receptors are activated by innocuous mechanical and thermal stimulation, respectively; the mechanoeffects are transmitted by both A-d and C fibers and the thermal effects only by C fibers. The polymodal afferents are most effectively excited by noxious or tissue-damaging stimuli, but they can respond as well to both mechanical and thermal stimuli and to chemical mediators such as those associated with inflammation. Moreover, certain A-d fibers respond to light touch, temperature, and pressure as well as to pain stimuli and are capable of discharging in proportion to the intensity of the stimulus. The stimulation of single fibers by intraneural electrodes indicates that they can also convey information concerning the nature and location of the stimulus (local sign). These observations on the polymodal functions of A-d and C fibers would explain the earlier observations of Lele and Weddell that modes of sensation other than pain can be evoked from structures such as the cornea, which is innervated solely by free nerve endings.
The peripheral afferent pain fibers of both A-d and C types have their cell bodies in the dorsal root ganglia; central extensions of these nerve cells project, via the dorsal root, to the dorsal horn of the spinal cord (or, in the case of cranial pain afferents, to the nucleus of the trigeminal nerve, the medullary analogue of the dorsal horn). The pain afferents occupy mainly the lateral part of the root entry zone. Within the spinal cord, many of the thinnest fibers (C fibers) form a discrete bundle, the tract of Lissauer (Fig. 8-1A). That Lissauer's tract is predominantly a pain pathway is shown (in animals) by the ipsilateral segmental analgesia that results from its transection, but it contains deep sensory, or propriospinal, fibers as well. Although it is customary to speak of a lateral and medial division of the posterior root (the former contains small pain fibers and the latter, large myelinated fibers), the separation into discrete functional bundles is not complete, and in humans the two groups of fibers cannot be differentially interrupted by selective rhizotomy.




Figure 8-1 A. Spinal cord in transverse section, illustrating the course of the afferent fibers and the major ascending pathways. Fast-conducting pain fibers are not confined to the spinothalamic tract but are scattered diffusely in the anterolateral funiculus. B. Transverse section through the sixth cervical segment of the spinal cord of the cat, illustrating the subdivision of the gray matter into laminae according to Rexed. LM and VM, lateromedial and ventromedial groups of motor neurons.


Dermatomic Distribution of Pain Fibers
Each sensory unit (the sensory nerve cell in the dorsal root ganglion, its central and peripheral extensions, and cutaneous and visceral endings) has a unique topography that is maintained throughout the sensory system from the periphery to the sensory cortex. The discrete segmental distribution of the sensory units permits the construction of sensory maps, so useful to clinicians. This aspect of sensory anatomy is elaborated in the next chapter, which includes maps of the sensory dermatomes and cutaneous nerves. However, as a means of quick orientation to the topography of peripheral pain pathways, it is useful to remember that the facial structures and anterior cranium lie in the fields of the trigeminal nerves; the back of the head, second cervical; the neck, third cervical; the epaulet area, fourth cervical; the deltoid area, fifth cervical; the radial forearm and thumb, sixth cervical; the index and middle fingers, seventh cervical; the little finger and ulnar border of hand and forearm, eighth cervical–first thoracic; the nipple, fifth thoracic; the umbilicus, tenth thoracic; the groin, first lumbar; the medial side of the knee, third lumbar; the great toe, fifth lumbar; the little toe, first sacral; the back of the thigh, second sacral; and the genitoanal zones, the third, fourth, and fifth sacrals. The distribution of pain fibers from deep structures, though not fully corresponding to those from the skin, also follows a segmental pattern. The first to fourth thoracic nerve roots are the important sensory pathways for the heart and lungs; the sixth to eighth thoracic, for the upper abdominal organs; and the lower thoracic and upper lumbar, for the lower abdominal viscera.
The Dorsal Horn
The afferent pain fibers, after traversing Lissauer's tract, terminate in the posterior gray matter or dorsal horn, predominantly in the marginal zone. Most of the fibers terminate within the segment of their entry into the cord; some extend ipsilaterally to one or two adjacent rostral and caudal segments; and some project, via the anterior commissure, to the contralateral dorsal horn. The cytoarchitectonic studies of Rexed in the cat (the same organization pertains in primates and probably in humans) have shown that second-order neurons, the sites of synapse of afferent sensory fibers in the dorsal horn, are arranged in a series of six layers or laminae (Fig. 8-1B). Fine, myelinated (A-d) fibers terminate principally in lamina I of Rexed (marginal cell layer of Waldeyer) and also in the outermost part of lamina II; some A-d pain fibers penetrate the dorsal gray matter and terminate in the lateral part of lamina V. Unmyelinated (C) fibers terminate in lamina II (substantia gelatinosa). Yet other cells that respond to painful cutaneous stimulation are located in ventral horn laminae VII and VIII. The latter neurons are responsive to descending impulses from brainstem nuclei as well as segmental sensory impulses. From these cells of termination, second-order axons connect with ventral and lateral horn cells in the same and adjacent spinal segments and subserve both somatic and autonomic reflexes. The main bundle of secondary neurons subserving pain sensation projects contralaterally (and to a lesser extent ipsilaterally) to higher levels.
In recent years, a number of important observations have been made concerning the mode of transmission and modulation of pain impulses in the dorsal horn and brainstem. Excitatory amino acids (glutamate, aspartate) and nucleotides such as adenosine triphosphate (ATP) are the putative transmitters at terminals of primary A-d sensory afferents. Also, A-d pain afferents, when stimulated, release several neuromodulators that play a role in the transmission of pain sensation. Slower neurotransmission by C neurons involves other substances, of which the most important is the 11–amino acid peptide known as substance P. In animals, substance P has been shown to excite nociceptive dorsal root ganglion and dorsal horn neurons; furthermore, destruction of substance P fibers produces analgesia. In patients with the rare condition of congenital neuropathy and insensitivity to pain, there is a marked depletion of dorsal horn substance P.
A large body of evidence indicates that opiates are important modulators of pain impulses that are relayed through the dorsal horn and centers in the medulla and pons. Thus, opiates have been noted to decrease substance P; at the same time, flexor spinal reflexes, which are evoked by segmental pain, are reduced. Opiate receptors of three types are found on both presynaptic primary afferent terminals and postsynaptic dendrites of small neurons in lamina II. Moreover, lamina II neurons, when activated, release enkephalins, endorphins, and dynorphins—all of which are endogenous, morphine-like peptides that bind specifically to opiate receptors and inhibit pain transmission at the dorsal horn level. The subject of pain modulation by opiates and endogenous morphine-like substances is elaborated further on.
Spinal Afferent Tracts for Pain
Lateral Spinothalamic Tract As indicated above, axons of secondary neurons that subserve pain sensation originate in laminae I, II, V, VII, and VIII of the spinal gray matter. The principal bundle of these axons decussates in the anterior spinal commissure and ascends in the anterolateral fasciculus to terminate in several brainstem and thalamic structures (Fig. 8-2). It is of clinical consequence that the axons from each dermatome decussate one to three segments above the level of root entry; in this way a discrete lesion of the lateral spinal cord creates a loss of pain and thermal sensation of the contralateral trunk, the dermatomal level of which is two to three segments below that of the spinal cord lesion. As the ascending fibers cross the cord, they are added to the inner side of the spinothalamic tract (the principal afferent pathway of the anterolateral fasciculus), so that the longest fibers from the sacral segments come to lie most superficially and fibers from successively more rostral levels occupy progressively deeper positions (Fig. 8-3). This somatotopic arrangement is of importance to the neurosurgeon insofar as the depth to which the funiculus is cut will govern the level of analgesia that is achieved; for the neurologist, it provides an explanation of the “sacral sparing” of sensation created by centrally placed lesions of the spinal cord.




Figure 8-2 The main somatosensory pathways. Offsets from the ascending anterolateral fasciculus (spinothalamic tract) to nuclei in the medulla, pons, and mesencephalon and nuclear terminations of the tract are indicated in Fig. 8-4.






Figure 8-3 Spinal cord showing the segmental arrangement of nerve fibers within major tracts. On the left side are indicated the “sensory modalities” that appear to be mediated by the two main ascending pathways. Note the broad zone close to the gray matter occupied by propriospinal fibers. C, cervical; L, lumbar; S, sacral; Th, thoracic. (Adapted by permission from Brodal A: Neurological Anatomy, 3rd ed. New York, Oxford University Press, 1981.)






Figure 8-4 The paleospinothalamic tract is illustrated on the right. This is a slow-conducting multineuron system that mediates poorly localized pain from deep somatic and visceral structures. On the left is the major descending inhibitory pathway, derived mainly from the periaqueductal gray matter and brainstem raphe nuclei. It modulates pain input at the dorsal horn level.


Other Spinocerebral Afferent Tracts In addition to the lateral spinothalamic tract—the fast-conducting pathway that projects directly to the thalamus—the anterolateral fasciculus of the cord contains several more slowly conducting, medially placed systems of fibers. One such group of fibers projects directly to the reticular core of the medulla and midbrain and then to the medial and intralaminar nuclei of the thalamus; this group of fibers is referred to as the spinoreticulothalamic or paleospinothalamic pathway (Fig. 8-4). At the level of the medulla, these fibers synapse in the nucleus gigantocellularis; more rostrally, they connect with nuclei of the parabrachial region, midbrain reticular formation, periaqueductal gray matter, and hypothalamus. A second, more medially placed pathway ascends to the brainstem reticular core via a series of short interneuronal links. It is not clear whether these spinoreticular fibers are collaterals of the spinothalamic tracts, as Cajal originally stated, or whether they represent an independent system, as more recent data seem to indicate. Probably both statements are correct. There is also a third, direct spinohypothalamic pathway. All three spinoreticular fiber systems lie in the posteromedial part of the lateral column. The conduction of diffuse, poorly localized pain arising from deep and visceral structures (gut, periosteum) has been ascribed to these pathways. Melzack and Casey have proposed that this fiber system (which they refer to as paramedian), with its diffuse projection via brainstem and thalamus to the limbic and frontal lobes, subserves the affective aspects of pain, i.e., the unpleasant feelings engendered by pain. It is evident that these spinoreticulothalamic pathways continue to evoke the psychic experience of pain even when the direct (anterolateral) spinothalamic pathways have been interrupted. However, it is the lateral pathway, which projects to the ventroposterolateral (VPL) nucleus of the thalamus and thence to discrete areas of the sensory cortex, that subserves the sensory-discriminative aspects of pain, i.e., the processes that underlie the localization, quality, and possibly the intensity of the noxious stimulus. Also, the pathways for visceral pain from the esophagus, stomach, small bowel, and proximal colon are carried largely in the vagus nerve and terminate in the nucleus of the solitary tract (NTS) before projecting to the thalamus, as described below. Other abdominal viscera still activate the NTS when the vagus is severed in animals, probably passing through the splanchnic plexus.
It should be emphasized that the foregoing data concerning the cells of termination of cutaneous nociceptive stimuli and the cells of origin of ascending spinal afferent pathways have all been obtained from studies in animals (including monkeys). In humans, the cells of origin of the long (direct) spinothalamic tract fibers have not been fully identified. Information about this pathway in humans has been derived from the study of postmortem material and from the examination of patients subjected to anterolateral cordotomy for intractable pain. As mentioned above, unilateral section of the anterolateral funiculus produces a relatively complete loss of pain and thermal sense on the opposite side of the body, extending to a level two or three segments below the lesion. After a variable period of time, pain sensation usually returns, probably being conducted by pathways that lie outside the anterolateral quadrants of the spinal cord and which gradually increase their capacity to conduct pain impulses. One of these is a longitudinal polysynaptic bundle of small myelinated fibers in the center of the dorsal horn (the dorsal intracornual tract); another consists of axons of lamina I cells that travel in the dorsal part of the lateral funiculus.
Thalamic Terminus of Pain Fibers
The direct spinothalamic fibers separate into two bundles as they approach the thalamus. The lateral division terminates in the ventrobasal and posterior groups of nuclei. The medial contingent terminates mainly in the intralaminar complex of nuclei and in the nucleus submedius. Spinoreticulothalamic (paleospinothalamic) fibers project onto the medial intralaminar (primarily parafascicular and centrolateral) thalamic nuclei; i.e., they overlap with the terminations of the medially projecting direct spinothalamic pathway. Projections from the dorsal column nuclei, which have a modulating influence on pain transmission, are mainly to the ventrobasal and ventroposterior group of nuclei. Each of the four thalamic nuclear groups that receives nociceptive projections from the spinal cord has a distinct cortical projection, and each is thought to play a different role in pain sensation (see below).
One practical conclusion to be reached from these anatomic and physiologic studies is that at thalamic levels, fibers and cell stations transmitting the nociceptive impulses are not organized into discrete loci. In general, neurophysiologic evidence indicates that as one ascends from peripheral nerve to spinal, medullary, mesencephalic, thalamic, and limbic levels, the predictability of neuron responsivity to noxious stimuli diminishes. Thus it comes as no surprise that neurosurgical procedures for interrupting afferent pathways become less and less successful at progressively higher levels of the brainstem and thalamus.
Thalamocortical Projections
The ventrobasal thalamic complex and the ventroposterior group of nuclei project to two main cortical areas: the primary sensory (postcentral) cortex (a small number terminate in the precentral cortex) and the upper bank of the sylvian fissure. These cortical areas are described more fully in Chap. 9, but it can be stated here that they are concerned mainly with the reception of tactile and proprioceptive stimuli and with all discriminative sensory functions, including pain. The extent to which either cortical area is activated by thermal and painful stimuli is uncertain. Certainly, stimulation of these (or any other) cortical areas in a normal, alert human being does not produce pain. The intralaminar nuclei, which also project to the hypothalamus, amygdaloid nuclei, and limbic cortex, probably mediate the arousal and affective aspects of pain and the autonomic responses.
Thalamic and cerebral cortical localization of visceral sensation is not well known. However, cerebral evoked potentials and increased cerebral blood flow (by PET studies) have been demonstrated in the thalamus and pre- and postcentral gyri of patients undergoing rectal balloon distention (Silverman et al; Rothstein et al).
Descending Pain-Modulating Systems
Of great importance was the discovery of a system of descending fibers and way stations that modulate activity in nociceptive pathways. The one system that has been studied most extensively emanates from the frontal cortex and hypothalamus and projects to cells in the periaqueductal region of the midbrain and then passes to the ventromedial medulla. From there it descends in the dorsal part of the lateral fasciculus of the spinal cord to the posterior horns (laminae I, II, and V; see further discussion under “Endogenous Pain-Control Mechanisms” and Fig. 8-5). Several other descending pathways, noradrenergic and serotoninergic, arise in the locus ceruleus, dorsal raphe nucleus, and nucleus reticularis gigantocellularis and are also important modifiers of the nociceptive response. The significance of these pain-modulating pathways is discussed further on.