Chapter 5: Somatic Sensation: Spinal Systems for Pain, Temperature, and Itch

Pain, temperature, and itch are our protective senses. Stimuli that evoke these sensations are good predictors of tissue harm. We touch a hot stove and withdraw our hand quickly to prevent a burn. We sense the itch of a mosquito bite and quickly swat at it to prevent further biting. Temperature brings us out of the cold or to seek shade when it is hot outside. Pain of a more persistent or recurring nature typically brings a patient to visit a physician, who will use this information diagnostically. Persistent itch can signal liver disease.

The stimuli that produce pain, temperature, and itch are sensed by specific sets of sensory receptor neurons that innervate all of our body's tissues—from the skin on the surface to our muscles, bones, and visceral organs, internally—to ensure the best possible protection. These sensory receptor neurons have specific connections with central nervous system structures that, when they become active, orchestrate a complex set of physiological and behavioral events. The evoked perceptions allow us to recognize precisely stimulus modality and where on our body it occurred. The emotions produced by the protective senses help us identify the context in which the stimuli were received, the negative valance of abdominal pain after eating tainted food or the positive side of a cool tropical breeze. The protective senses mobilize our actions, to help ensure removal of the stimulus, to prevent bodily harm. Not surprisingly, the pain, temperature, and itch systems connect directly with diverse brain regions, much more so than for touch. Unique to our protective senses is that they engage areas of the cerebral cortex that are more known for their involvement in emotions than sensation. Unfortunately, our protective senses can be easily fooled; they can be activated into a persistent state of false alarm.

In this chapter, we will examine the neural systems for pain, temperature, and itch. We first examine the systems in overview and then consider the different levels of sensory processing, from the periphery to the cerebral cortex. We will focus on pain because more is known about its anatomical substrates. However, as we learn more about temperature sense and itch, it appears that all three protective senses engage similar spinal cord and brain circuits.

Pain, Temperature, and Itch Are Mediated by the Anterolateral System

The anterolateral system (Figure 5–2A, B) is a collection of ascending pathways that travel in the anterior portion of the lateral column of the spinal cord and synapse in different brain regions. Surgical destruction of the anterolateral system spares touch and limb position senses but renders people insensitive or less sensitive to pain. Termed an anterolateral cordotomy, this procedure was commonly used to treat intractable pain before effective analgesics became available. The anterolateral system also mediates a residual, or crude, sense of touch after damage to the dorsal column-medial lemniscal system. Normally, this form of touch is thought to play a role in a sense of well being; it is sometimes termed sensual touch.

Sensory receptor neurons sensitive to noxious (ie, painful), pruritic (ie, itch provoking), and thermal stimuli provide the major sensory inputs to the anterolateral system. The anterolateral system's first relay is in the dorsal horn of the spinal cord (Figure 5–2A, B). Here, sensory fibers synapse on ascending projection neurons of the anterolateral systems. The axon of the ascending projection neuron of the anterolateral systems crosses the midline in the spinal cord. Curiously, for both the anterolateral and dorsal column–medial emniscal systems, the axon of the second neuron in the circuit decussates.

The anterolateral system comprises multiple pathways for several distinctive functions. We will focus on the role of these pathways in three aspects of pain but, as indicated above, there are many similarities with temperature and itch: (1) sensory-discriminative aspects of pain, (2) emotional aspects of pain, and (3) arousal and feedback control of pain transmission. Central to the sensory-discriminative aspects of pain—where the stimulus is located and its intensity—is the spinothalamic projection to the ventral posterior lateral nucleus, which in turn transmits information to the primary somatic sensory cortex (Figure 5–2A). This projection is somatotopically organized. Functional imaging studies have shown that this projection encodes the physical intensity of the stimulus, not the person's subjective impression of intensity.

Whereas nonpainful stimuli can have emotional overtones, they need not. By contrast, pain seems always to carry a negative emotion. For this reason, much of the pain pathway also targets subcortical and cortical centers for emotions (Figure 5-2B; see Chapter 16). Spinothalamic projections to the ventromedial posterior nucleus, which projects to the posterior insular cortex, and the medial dorsal nucleus of the thalamus, which transmits information to the anterior cingulate gyrus, are important in the emotional aspects of the stimulus (Figure 5–2B). The insular cortex projection is also thought to be important for perception of stimulus quality. The anterior cingulate pain projection is tied closely to the negative valence of pain. Interestingly, the anterior cingulate cortex becomes active both during actual pain (ie, noxious stimulation) and during emotional pain, feeling hurt (see Figure 2-7B).

The spinoreticular tract engages a subcortical emotional pathway (Figure 5–2B). This path relays in the parabrachial nucleus that, in turn, targets the amygdala (see Figure 1-10A). The amygdala has diverse projections to cerebral hemisphere structures, thereby capable of influencing our thoughts, emotions, and behaviors. The amygdala, together with the insular cortex, helps organize our behavioral responses that accompany pain, such as the increase in blood pressure or rubbing the injured site.

Arousal and feedback control of pain transmission center on the brain stem. Nuclei in the brain stem reticular formation in the pons and medulla receive sensory information of various sorts—painful as well as nonpainful somatic stimuli, sounds, and sights—and use this information to regulate arousal. The spinoreticular tract brings information about pain to these nuclei. Many of these reticular formation neurons project to the intralaminar thalamic nuclei that have broad projections to the basal ganglia and cerebral cortex for arousal. The spinomesencephalic tract terminates primarily in the midbrain tectum and periaqueductal gray matter. The projection to the tectum integrates somatic sensory information with vision and hearing for orienting the head and body to salient, notably noxious, stimuli (see Chapter 7). Projections to the periaqueductal gray matter play a role in the feedback regulation of pain transmission in the spinal cord (see section below on descending control of pain transmission).

Visceral Pain Is Mediated by Dorsal Horn Neurons Whose Axons Ascend in the Dorsal Columns

There is a special pathway for pain from caudal visceral structures—such as in the pelvic region and parts of the lower gut—that is different from that of pain originating from other body parts (Figure 5–2C). Rather than synapse on dorsal horn neurons that send their axons into the anterolateral white matter, dorsal horn visceral pain neurons send their axons into the medial portion of the dorsal columns, the gracile column. Recall that most axons in the dorsal columns, approximately 85%, are the central branches of mechanoreceptors (Chapter 4); the remaining 15% receive nociceptive information. Surprisingly, the visceral pain pathway follows a course similar to the mechanosensory pathway, synapsing in the dorsal column nuclei, decussating in the medulla, ascending in the brain stem in the medial lemniscus, and synapsing within the thalamus. There is a significant difference; the visceral pain path synapses in separate portions of the dorsal column nuclei and thalamus than the mechanosensory pathway. Much less is known of this potentially very important pathway than the anterolateral pathways.

Small-Diameter Sensory Fibers Mediate Pain, Temperature, and Itch

Nociceptors are sensory receptor neurons that are sensitive to noxious or tissue-damaging stimuli and mediate pain. These receptor neurons respond to chemicals released from traumatized tissue. There are three principal classes of nociceptor: thermal, mechanical, and polymodal. Thermal nociceptors are activated by temperatures less than about 5° and greater than 45°. Mechanical nociceptors are activated by a tissue-damaging mechanical stimulus, such as a needle. Polymodal nociceptors are activated by noxious thermal or mechanical stimuli. Itch-sensitive receptors, or pruriceptors, respond to histamine. Itch is evoked when histamine is injected intradermally. Receptor neurons sensitive to cold or warmth are termed thermoreceptors.

The morphology of these classes of receptor neurons is simple; they are bare nerve endings (see Figure 4–3). In contrast to mechanoreceptors, which have a large diameter and thickly myelinated axon (A-α and A-β), nociceptors, thermoreceptors, and pruriceptors have small-diameter axons, which fall into the A-δ and C-fiber categories (see Table 4–1). Nociceptors are both thinly myelinated (A-δ) and unmyelinated (C fibers). A brief noxious stimulus evokes initially a sharp, pricking pain, sometimes termed "fast" pain, mediated by A-δ nociceptors followed by a dull burning pain, sometimes termed "slow" pain, mediated by C-fiber nociceptors. Thermoreceptor axons also conduct action potentials in the A-δ and C-fiber ranges. Pruriceptors are C-fibers only.

There has been much research on the mechanisms of transduction of noxious stimuli into depolarizing sensory potentials. Important among the various membrane receptors that nociceptors have are the diverse members of the transient receptor potential (TRP) receptors. For example, TRPV1, TRPV2, TRPV3, and TRPV4 receptors are responsible for thermal sensitivity in the warm (ie, innocuous) to hot (noxious) range. TRPV1 receptors mediate the hot of capsaicin, and TRPV2 receptors are activated by very high temperatures (TRPV2). By contrast, TRPM8 receptors are activated at very low temperatures and by certain chemical, such as menthol (TRPM8). There are several candidate membrane receptors for mechanotransduction in mechanonociceptors. Pruriceptors are sensitive to histamine.

Pain sensitivity naturally changes, and much of this plasticity occurs at the periphery. Nociceptors can become sensitized—that is, develop a memory of prior injury—and the pain system becomes more responsive. This can be produced by factors that are released at the injury site as a consequence of the tissue damage and ensuing inflammation. Hyperalgesia is an exaggerated response to a noxious stimulus. Allodynia is feeling pain to a stimulus that normally does not produce pain, such as light touch. Pain also can get out of control, signaling a persistent "false alarm." These chronic pain states can be debilitating. They have both peripheral and central nervous system components, including maladaptive plasticity in the dorsal horn (see next section) and abnormal modulatory signals from the brain.

Small-Diameter Sensory Fibers Terminate Primarily in the Superficial Laminae of the Dorsal Horn

Small-diameter axons—which subserve pain, itch, and temperature senses—enter the spinal cord in Lissauer tract, the white matter region that caps the dorsal horn (see Figure 5–4). Note that although Lissauer tract is part of the white matter, it stains lightly because its axons either have a thin myelin sheath or are unmyelinated. Within the tract the fibers bifurcate and ascend and descend before they branch into the gray matter.

Small-diameter fibers have a very specific termination pattern. To better understand the significance of this pattern, we first need to consider the laminar organization of the spinal gray matter (Figure 5–3). Similar to other areas of the central nervous system, spinal cord neurons are clustered. The Swedish neuroanatomist Bror Rexed further recognized that neuron clusters in the spinal cord often formed flattened sheets, termed Rexed laminae (Table 5–1; Figure 5–3), that run parallel to the long axis of the spinal cord. He distinguished 10 laminae. The dorsal horn is now regarded to comprise laminae I through V and the ventral horn, laminae VI through IX. Lamina X comprises the gray matter surrounding the central canal. However, for functional reasons we also distinguish laminae VI, the dorsal part of VII, and X from laminae VIII and IX. Many interneurons important for movement control are located in laminae VI, VII, and X, and this is termed the intermediate zone; motor neurons that innervate axial, proximal, and distal muscles are located ventral to the intermediate zone, in laminae VIII and IX.

Like Brodmann's areas of the cerebral cortex (Figure 1-19), neurons clustered according to Rexed laminae have a functional organization. Laminae I and II receive information from small-diameter myelinated (A-δ) fibers and unmyelinated (C) fibers only, indicating a selective role in pain, temperature, and itch processing. By contrast, laminae III and IV receive only large-diameter (A-α, A-β) fiber terminations. These laminae serve mechanosensory and reflex functions. Lamina V receives information from both small- and large-diameter fibers (Figure 5–3), enabling the neurons there to process a broad range of somatic stimulus intensities, from light touch to pain. The deeper laminae, VI through IX, tend to receive much less afferent fiber information directly. There is one important exception; primary muscle spindle receptors and Golgi tendon organs terminate in the motor regions (laminae VII and IX); and the primary muscle spindle receptors synapse directly on motor neurons.

Anterolateral System Projection Neurons Are Located in the Dorsal Horn and Decussate in the Ventral Commissure

The laminar organization of the dorsal horn is also important for the projections to the brain stem and thalamus. The pathway to thalamic nuclei important for pain, itch, and temperature sensations originates primarily from neurons in lamina I, which receives direct input from small-diameter sensory fibers (Figure 5–3), and lamina V, where neurons receive both small and large fiber inputs and respond to a range of stimuli. The spinal cord neurons whose axons project to the intralaminar nuclei and reticular formation of the pons and medulla, involved primarily in arousal, are located more ventrally in the gray matter, in laminae VI through VIII. The projection to the midbrain, important for orienting to salient stimuli and pain suppression, also originates from neurons in laminae I and V, similar to the projection to the ventral posterior lateral nucleus.

Most axons of the anterolateral system decussate in the spinal cord before ascending to the brain stem or thalamus (Figures 5–2 and 5–3). Decussations occur in commissures, in this case in the ventral (anterior) commissure, ventral to the central canal (Figure 5–4A). During early development, this region corresponded to the floor plate, an important site for guiding spinal axons across the midline. Developing axons are attracted to the midline at the floor plate. However, once the axons cross the midline, there is a molecular switch. The attraction they had for the midline floor plate is converted to a repulsion that prevents the axons from recrossing. While much is known about how axons cross the midline, why they cross is not known. Once on the opposite side, the developing axons are now attracted to grow toward particular regions of the white matter, where they ascend to the brain. Less is known about long-distance axon guidance toward the brain than decussation. The location of the ascending axons of the anterolateral system is revealed by examining the degenerated area in the lateral column in Figure 5–4C. Although the anterolateral system is somatotopically organized (Figure 5–4B), it is not as precise as that for the dorsal columns and only a trend is apparent. Axons transmitting sensory information from more caudal segments are located lateral to those from more rostral segments.

Neurons in the dorsal horn in the sacral, lumbar, and thoracic spinal cord receive nociceptive inputs from visceral structures. Rather than projecting their axon to the contralateral white matter, they project to the ipsilateral gracile fascicle and follow a course very similar to the mechanosensory pathway (Figure 5–2C). Many lamina V neurons in the sacral, lumbar, and thoracic spinal cord receive convergent information from visceral nociceptors and cutaneous receptors. This provides the anatomical substrate for "referred pain," whereby pain resulting from visceral tissue damage is perceived as originating from a portion of the body surface. For example, pain associated with a myocardial infarction is felt on the left arm and chest, possibly because sensory fibers from the heart sensing a lack of tissue oxygen converge onto neurons in the upper cervical spinal cord.

Vascular Lesions of the Medulla Differentially Affect Somatic Sensory Function

Axons of the anterolateral system ascend along the anterolateral margins of the white matter of the spinal cord (Figure 5–4A). When the fibers reach the medulla, they shift dorsally, being displaced by the large inferior olivary nucleus (Figure 5–6A). As we learned in Chapter 3, the medial and dorsolateral medulla receive their arterial supplies from small direct branches of the vertebral artery and the posterior inferior cerebellar artery (PICA), respectively (Figure 5–6A). Occlusion of the PICA damages the ascending pain, temperature, and itch fibers but not the medial lemniscus. A patient who experiences an infarction of the PICA can have diminished pain sensation on the limbs and trunk but unaffected touch sense. The sensory loss is contralateral to the side of the lesion because the axons of the anterolateral system decussate in the spinal cord (Figure 5–5). (Such sensory loss is one of multiple neurological signs that comprise the lateral medullary, or Wallenberg, syndrome, which is discussed further in Chapters 6 and 15.)

Farther rostrally in the pons and midbrain, the anterolateral system joins the medial lemniscus (Figure 5–7). The spinothalamic tract, like the medial lemniscus, courses through the pons and midbrain en route to the thalamus. The spinoreticular tract terminates centrally within the medulla and pons, in a region termed the reticular formation. Once thought to subserve a discrete set of arousal-related functions, what is termed the reticular formation is a heterogeneous collection of nuclei serving many somatic, visceral, and regulatory functions. An important projection of the spinoreticular tract is to the parabrachial nucleus (Figure 5–7B). This is a key relay for visceral afferent information—both nociceptive and innocuous—to the hypothalamus and amygdala. One projection of the spinomesencephalic tract that is important for orienting to somatic stimuli is to the superior colliculus (Figure 5–7A; see Chapter 7).

Descending Pain Suppression Pathways Originate From the Brain Stem

While all sensation is mutable, being critically dependent on context and experience, modulation of pain perception is particularly salient and clinically relevant. Consider how pain becomes diminished during physical combat or in childbirth. Pain suppression may be a survival mechanism that allows people to function better despite sudden pain. The circuit for pain suppression uses serotonergic and noradrenergic mechanisms to inhibit pain transmission in the dorsal horn (Figure 5–8). Beginning in the forebrain, structures involved in emotions as well as pain processing—including the amygdala, hypothalamus, insular cortex, and anterior cingulate cortex—project to excitatory glutamatergic neurons of the periaqueductal gray matter (Figures 5–7 and 5–8) that, in turn, regulate a collection of medullary neurons in the raphe nuclei that use serotonin as their neurotransmitter (5-HT; Figure 5–8, inset). The raphe nuclei give rise to a descending serotonergic pathway to the spinal cord. Similarly, other regions in the brain stem, including the locus ceruleus (see Figure 2–3) and the lateral medullary reticular formation, give rise to descending noradrenergic projections to the spinal cord (NA; Figure 5–8). Pain transmission in the dorsal horn is suppressed by promoting the inhibitory actions of dorsal horn interneurons, including those using enkephalin as their neurotransmitter, decreasing the capacity for nociceptors to activate their postsynaptic targets, and by inhibiting pain ascending projection neurons directly.

Three Separate Nuclei in the Thalamus Process Pain, Temperature, and Itch

The ventral posterior nucleus is an important recipient of both the anterolateral system and the dorsal column system for visceral pain (Figure 5–2C). Although both the mechanosensory and the pain, temperature, and itch projections terminate in the ventral posterior lateral nucleus, their terminal fields hardly overlap, an example of functional localization within the central nervous system. The mechanosensory projections tend to be located rostral to the projections for pain, temperature, and itch.

The ventromedial posterior nucleus (Figure 5–9A) is caudal to the ventral posterior nucleus. It projects to the insular cortex (Figure 5–10), which, as discussed, is important for perception of the quality and intensity of pain, temperature, and itch, and in mediating behavioral and autonomic responses. The medial dorsal nucleus (Figure 5–9B) also receives spinothalamic input and projects to the anterior cingulate gyrus (Figure 5–10), which is involved in the emotional aspects of somatic sensory stimulation. The intralaminar nuclei (see Figure 2–13) also receive spinothalamic input, visceral pain input from the dorsal column nuclei, as well as information from the reticular formation. However, the pain functions of the intralaminar nuclei are not understood. The intralaminar nuclei are diffuse-projecting and may participate in arousal and attention (see Table 2–1).

Limbic and Insular Areas Contain the Cortical Representations of Pain, Itch, and Temperature Sensations

The ascending pain, temperature, and itch pathways influence wide areas of the cerebral cortex. For acute pain, which has been studied most thoroughly, a complex set of areas becomes activated: the primary and secondary somatic sensory areas, the insular cortex, the anterior cingulate cortex, and the prefrontal cortex. To this, one can add diverse areas of the thalamus and the amygdala. This complex set of brain structures has been termed the "pain matrix." Many of these areas are also activated during thermal stimulation and itch.

Noninvasive imaging studies in humans presented with noxious stimuli, as well as studies in anesthetized animals, are beginning to elucidate the particular contributions of individual components of the pain matrix. The primary somatic sensory cortex is thought to be important in localizing the stimulus and discerning intensity. The insular cortex (Figures 5–10 and 5–11) is important in discriminating the quality and intensity of the stimulus, and possible affective aspects of pain. Importantly, the insular cortex is the most consistently activated of all cortical areas during painful stimuli. The pain representation in the insular cortex, together with adjoining representations of taste and internal organs (see Chapters 6 and 9), may also be part of a network of cortical regions mediating body homeostasis. These areas also can regulate behavioral and autonomic responses to pain. The anterior cingulate gyrus (Brodmann's area 24; see Figure 2–19) is part of the limbic system for emotions. Not surprisingly, the anterior cingulate becomes more activated when painful and thermal stimuli are judged to be more unsettling and unpleasant. Interestingly, the same cingulate area that is important in signaling the emotional aspects of pain is also important for the emotional aspects of somatic sensory stimulation and in the "hurt" of social exclusion (Figure 2-7B).

Sensory Receptor Neurons

The anterolateral system mediates pain, temperature, and itch senses and crude touch (Figure 5–2A, B). Visceral pain is processed by a small contingent of dorsal column axons (Figure 5–2C). Dorsal root ganglion neurons sensitive to noxious stimuli, warmth, cold, or itch (histamine) have bare nerve endings and small-diameter axons (A-δ; C; see Table 4–1).

Spinal Cord

The axons of dorsal root ganglion neurons enter the spinal cord via the dorsal roots. A dermatome is the area of skin innervated by a single dorsal root (see Figure 4–5). Small-diameter fibers enter the spinal cord and ascend and descend in Lissauer tract (Figures 5–2 and 5–4); they eventually terminate in the gray matter of the spinal cord (Figure 5–3). The axons of the anterolateral system derive from dorsal horn neurons and decussate in the ventral (anterior) commissure (Figures 5–2, 5–3, and 5–5). The anterolateral system ascends in the lateral column (Figures 5–4). Ascending visceral fibers ascend medially in the dorsal columns, in the gracile fascicle (Figure 5–4). Spinal cord hemisection has a differential effect on the somatic sensory modalities caudal to the lesion, producing loss of touch and position senses on the side of the lesion and loss of pain and temperature senses on the opposite side (Figure 5–5).

Brain Stem

Fibers of the anterolateral system terminate in the reticular formation (Figure 5–6; spinoreticular tract), parabrachial nucleus (Figure 5–7), midbrain, including the periaqueductal gray matter (Figure 5–7; spinomesencephalic tract), and thalamus (spinothalamic tract) (Figures 5–7 and 5–9). Visceral pain fibers synapse in the gracile nucleus, in a separate region from mechanosensory fibers, and ascend to the thalamus in the medial lemniscus (Figures 5–6 and 5–7). Anterolateral system fibers receive their arterial supply in the medulla by PICA (Figure 5–6).

Descending Pain Modulatory Systems

Forebrain structures for emotions and pain processing—including the amygdala, hypothalamus, insular cortex, and anterior cingulate cortex—project to excitatory glutamatergic neurons of the periaqueductal gray matter (Figure 5–8). These neurons regulate serotonergic neurons in the raphe nuclei and noradrenergic neurons in the reticular formation that project to the dorsal horn (Figure 5–8). Pain transmission in the dorsal horn is suppressed by promoting the inhibitory actions of dorsal horn neurons.

Thalamus and Cerebral Cortex

Axons of the spinothalamic tract, and probably viscerosensory fibers, synapse in the three principal thalamic nuclei that, in turn, project to different cortical areas. The ventral posterior lateral nucleus (Figure 5–10), which projects to the primary somatic sensory cortex (Figures 5–10 and 5–11), is important for perception of stimulus intensity and location. The ventromedial posterior nucleus (Figure 5–9A), which projects to the insular cortex (Figures 5–10 and 5–11), is also important in stimulus perception as well as affective aspects of pain and thermal stimuli. The third nucleus, the medial dorsal nucleus (Figures 5–9 and 5–10), projects to the cingulate cortex (Figure 5–11) for the emotional responses to pain. The insular and anterior cortical regions are also important in the behavioral and autonomic responses to pain, temperature, and itch sensations and the emotions and memories these stimuli evoke.