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.