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.
Laminar termination patterns of primary sensory axon terminals in the dorsal horn. A-δ and C fibers terminate superficially in the dorsal horn, with a branch of the A-δ fiber also terminating in deeper layers. A-β fibers terminate in the deeper layers of the dorsal horn. However, the major A- β branch ascends in the dorsal column. Projection neurons of the anterolateral system are shown, located in laminae I and V. Their axons decussate in the ventral spinal commissure. Note that while laminae I-VI resemble flattened sheets, laminae VII-IX are more columnar-shaped. (Adapted from Rexed B. A cytoarchitectonic atlas of the spinal cord in the cat. J Comp Neurol, 1954;100:297-379.)
Spinal cord anatomy. A. Myelin-stained section showing key structures of the pain pathway. B. Drawing of spinal cord with somatotopy of the anterolateral system. C. Location of degenerated somatic sensory paths after a lumbar spinal cord injury.
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.
Table 5–1Correspondence between Rexed laminae and nuclei ||Download (.pdf) Table 5–1 Correspondence between Rexed laminae and nuclei
|Rexed lamina ||Spinal cord nucleus |
|Lamina I ||Marginal zone |
|Lamina II ||Substantia gelatinosa |
|Laminae III and IV ||Nucleus proprius |
|Lamina V ||Base of dorsal horn |
|Laminae VI and VII ||Intermediate zone |
|Lamina IX ||Motor nuclei |
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.
Box 5–1 The Patterns of Somatic Sensory Impairments After Spinal Cord Injury
Spinal cord injury results in deficits in somatic sensation and in the control of body musculature at the level of, and caudal to, the lesion. Motor deficits that follow such injury are considered in Chapter 10. Here, only somatic sensory deficits are considered. We will integrate our knowledge of the pain, as well as mechanosensory, pathways because traumatic injury to the spinal cord may not distinguish one system from another. In general, somatic sensory deficits after spinal injury have three major characteristics: (1) the sensory modality that is affected, for example, whether pain or touch is impaired on a particular body part, (2) the laterality, or side of the body where deficits are observed (ie, ipsilateral vs contralateral), and (3) the body regions affected. Damage to one half of the spinal cord, or hemisection, illustrates all three of these characteristic deficits (Figure 5–5). Spinal hemisection can occur, for example, when the cord is injured traumatically, such as with a gun-shot wound or when a tumor encroaches on the cord from one side. The sensory and motor deficits that follow spinal cord hemisection are collectively termed the Brown–Séquard syndrome.
Axons in the dorsal columns are ipsilateral to their origin in the spinal cord; hence, deficits in touch and limb position sense are present ipsilateral to the spinal cord lesion (Figure 5–5). In contrast, the axons of the anterolateral system decussate in the spinal cord. Therefore, pain and temperature senses are impaired on the side of the body that is contralateral to the lesion. (Note that itch is not usually tested but presumably also is impaired contralaterally.)
The spinal cord level at which injury occurs can be determined by comparing the distribution of sensory loss with the sensory innervation patterns of the dorsal roots (ie, the dermatomal maps; Figure 4–5). Because of the differences in the anatomical organization of the two systems mediating somatic sensations, a single level of spinal injury will result in different levels of sensory impairment for touch and pain sensations. For touch sensation, the most rostral dermatome in which sensation is impaired corresponds to the level of injury in the spinal cord. For pain sensation, the most rostral dermatome in which sensation is impaired is about two segments lower than the injured spinal cord level. This is because the axons of the anterolateral system decussate over a distance of one to two spinal segments before ascending to the brain stem and diencephalon. This is clinically significant because it gives the injured person more caudal protective sensory awareness, which can help in detecting debilitating events that would otherwise go unnoticed, such as pressure injuries.
A. The patterns of decussation of the dorsal column–medial lemniscal and anterolateral systems are illustrated in relation to spinal cord hemisection (Brown-Séquard syndrome). B. Because projection neurons of the anterolateral system ascend as they decussate, spinal hemisection produces a loss of pain, temperature, and itch one to two segments caudal to the lesion. In contrast, loss of mechanical sensations begins at the level of the lesion.
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.)
Myelin-stained section through mid-medulla (A) and corresponding MRI (B). The pattern of arterial perfusion of the rostral medulla is also shown in part A.
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).
Myelin-stained sections through the midbrain (A) and pons-midbrain junction (B).
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.
Pain modulatory system. Information from diverse forebrain regions converge onto the periaqueductal gray matter (PAG). The PAG, in turn, projects to serotonergic (5-HT) nuclei in the medulla, the raphe nuclei, as well as medullary noradrenergic (NA) nuclei in the reticular formation. Descending 5-HT and NA pathways promote inhibition in the spinal cord, thereby suppressing pain transmission.
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).
Myelin-stained sections through the thalamic pain nuclei. A. Posterior thalamus, which is the location of the ventral medial posterior nucleus. B. Medial dorsal nucleus and the ventral posterior nucleus. Note that the ventral posterior nucleus comprises two nuclear divisions. The ventral posterior lateral nucleus is for spinal somatic sensory processing and the ventral posterior medial nucleus is for the trigeminal system. C. Amygdala and hypothalamus.
Pain pathways and thalamo-cortical relations. A single schematic nociceptor is shown to project information to three thalamic nuclei, which in turn, project to three separate cortical areas. The ventral posterior nucleus projects to the primary somatic sensory cortex. The ventral medial posterior nucleus projects to the insular pain cortex. The medial dorsal nucleus, which has diverse frontal lobe projections, transmits pain information to the anterior cingulate cortex.
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).
Noxious stimulation activates many subcortical regions that, in turn, activate many cortical areas, which are termed the pain matrix. A. Salient features of the divergence of pain information to the brain stem and cortex are shown on a mid-sagittal brain view. These structures have been identified on the basis of brain imaging studies. The key cortical areas are: somatic sensory cortex, insular cortex, cingulate cortex, and prefrontal cortex. Motor cortex is also shown because it is important in voluntary motor responses evoked by painful stimuli. B. Semischematic drawing through the pain matrix structures: coronal slice is shown above three sagittal slices, whose plains are indicated in the coronal slice. (Based on the meta-analysis in Apkarian AV, Bushnell MC, Treede RD, Zubieta JK. Human brain mechanisms of pain perception and regulation in health and disease. Eur J Pain. 2005;9:463-484.)