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Sensory Transduction 403 tongue that are activated by the compound capsaicin. A capsaicin receptor has been cloned and shown to be a calcium-selective cation channel.122 The hot receptor, known as transient receptor potential (subfamily V, member 1), or TRP-V1, is also found in small diameter sensory fibers (C fibers) responding to noxious temperatures (see following section). Thus, nature has provided chili peppers with a chemical targeted to this receptor, possibly to discourage herbivores by activating pain fibers—a not entirely successful strategy in the case of humans with a preference for spicy foods. Pain and Temperature Sensation in Skin The somatosensory system includes a rich variety of encapsulated and free nerve endings that provide input from the body, the surface skin, as well as deeper tissues. Specialized receptors for fine touch and vibration are discussed in Chapter 21. Here we will examine the neural basis of pain and temperature sensation. These percepts arise largely from the activity of small caliber C fibers and Aδ fibers. The stimuli affect free nerve endings, without any accessory structures, and act largely through indirect mechanisms of transduction. One class of endings is activated selectively by noxious stimuli—mechanical injury, excessive heat or cold, or chemical damage. It is natural, then, to postulate a direct connection between activity in these fibers and the sensation of pain. The discovery of this separate population of nociceptors, together with the finding that low-threshold mechanoreceptors do not respond to painful stimuli, ruled out an earlier theory that pain results from the excessive mechanoreceptor stimulation. Indeed there is growing evidence for nociceptor submodalities; for example, a population of itch-specific afferent neurons.123 Temperature changes are transduced by free nerve endings through the activation of TRP ion channels. Channel permeability varies with changes in skin temperature. Four different TRP channels, TRPV1 to TRPV4, are activated over different warm temperature ranges124 (Figure 19.18). As already noted, TRPV1 is activated by noxious heating and is sensitive to capsaicin. TRPM8 is a Ca2+-permeable channel activated by lowering temperature.125 Menthol and eucalyptol also activate this channel, which explains the cooling sensation evoked by these compounds. Painful (or noxious, <17°C) cold requires the additional participation of TRPA1 channels.126 122 Caterina, M. J. et al. 1997. Nature 389: 816–824. 123 Liu, Q. et al. 2009. Cell 139: 1353–1365. 124 Lumpkin, E. A., and Caterina, M. J. 2007. Nature 445: 858–865. 125 Reid, G. 2005. Pflügers Arch. 451: 250–263. 126 Kwan, K. Y., and Corey, D. P. 2009. J. Gen. Physiol. 133: 251–256. (A) Anktm1 Trpm8 Trpv3 Trpv4 TRP domain (B) Channel activity Trpm8 (CMR1) Trpv4 Trpv3 Trpv1 (Vr1) Anktm1 0 10 Trpv2 (Vrl1) 20 30 40 Temperature (°C) Trpv1 Trpv2 Ankyrin domain FIGURE 19.18 TRP Channels and Temperature Coding. (A) TRP channels are composed of six putative membrane-spanning units and cytoplasmic amino and carboxyl termini. (B) ThermoTRPs have different thermal activation ranges. In some cases chemical compounds also activate the receptor, producing a sensation of cooling (menthol on Trpm8) or heating (chili on Trpv1). Activation curves averaged across multiple studies; dashed portions extrapolated. (After Patapoutian et al., 2003.) 50 ©2011 Sinauer Associates, Inc. This material cannot be copied, reproduced, manufactured or disseminated in any form without express written permission from the publisher. 404 Chapter 19 Activation and Sensitization of Nociceptors 127 Bevan, S., and Yeats, J. 1991. J. Physiol. 433: 145–161. 128 Cesare, P., and McNaughton, P. 1996. Proc. Natl. Acad. Sci. USA 93: 15435–15439. 129 Szallasi, A., and Blumberg, P. M. 1996. Pain 68: 195–208. 130 Waldmann, R. et al. 1997. Nature 386: 173–177. 131 Chen, C. C. et al. 1995. Nature 377: 428–431. 132 Lewis, C. et al. 1995. Nature 377: 432–435. 133 Cook, S. P. et al. 1997. Nature 387: 505–508. 134 Burgess, G. M. et al. 1989. J. Neurosci. 9: 3314–3325. 135 Gold, M. S. et al. 1996 Proc. Natl. Acad. Sci. USA 93: 1108–1112. 136 Adams, P. R., Brown, D. A., and Jones, S. W. 1983. Brit. J. Pharmacol. 79: 330–333. Nociception (the perception of noxious or damaging stimuli) arises from a combination of direct and indirect actions on peripheral sensors. Painful heat (hotter than about 43° C) causes nonspecific cation channels (TRPV1) to open in C fiber endings.127,128 Calcium and sodium ions enter and depolarize the cell, causing action potential generation. Prolonged exposure of these endings to capsaicin eventually causes calcium accumulation and cell death. For this reason capsaicin is used as a long-term analgesic, presumably relieving chronic pain by killing C fiber afferents.129 Acids also may act to open cation channels directly, and an acid-sensitive ion channel (ASIC) has been cloned from nociceptive neurons.130 Mechanical stimuli leading to skin damage can also produce direct activation of nociceptive endings. In addition to being activated directly by painful stimuli, nociceptors respond to chemical activators, such as ATP, released from damaged cells. One ATP receptor subunit (P2X3) occurs specifically in C fiber somata in dorsal root ganglia and may contribute to the structure of nociceptive ATP receptors in the sensory terminals.131–133 Cellular damage also leads to the release of cytoplasmic proteases, which then cleave serum proteins. In this manner the nine–amino acid peptide, bradykinin, is produced from kininogen, a ubiquitous inactive precursor. Bradykinin is a potent activator of C fiber endings. Unlike ATP, its effects are mediated by metabotropic receptors, rather than by direct action on membrane channels.134 Bradykinin and other chemicals in damaged skin also act to increase the excitability of (i.e., sensitize) nociceptive endings activated by other stimuli. For example, responses to noxious heat stimuli are larger and occur at a lower temperature than normal in the presence of bradykinin.128 Other inflammatory mediators include prostaglandins, serotonin, histamine, and substance P. Prostaglandin E2 and serotonin increase sensitivity by lowering the threshold for activation of voltage-gated sodium currents.135 Activated pain fibers release substance P not only from their synapses within the spinal cord (see Chapter 14), but also from their terminals in the skin. In the periphery, substance P may increase the excitability of C fibers by blocking K+ channels.136 The process of sensitization is accompanied by local vasodilatation and edema. The affected area becomes hyperalgesic, having a reduced threshold for pain. SUMMARY ■ Each type of sensory receptor responds preferentially to one type of stimulus energy, the adequate stimulus. ■ Short and long receptors differ morphologically and functionally. Short receptors encode stimulus intensity directly in the amplitude of the receptor potential. Long receptors take the additional step of converting the receptor potential amplitude into a frequency code of action potential firing. ■ The response of many receptors varies with the log of the stimulus intensity. This enables some receptor types to have a wide dynamic range. ■ Most sensory receptors adapt during maintained stimuli. Adaptation arises from both mechanical and electrical factors. In some receptors, very rapid adaptation makes them tuned to rapidly varying stimuli, such as vibration. ■ Mechanosensory hair cells of the inner ear couple movement directly to the gating of ion channels by physical connection. The tip link that connects adjacent stereocilia is stretched by deflection of the hair bundle and so pulls open an ion channel. ■ Calcium entry through the nonselective mechanotransduction channel of hair cells leads to adaptation and closure of the channel. ■ Olfactory neurons employ G protein–coupled membrane receptors that lead to the opening of cAMPgated cation channels in the plasma membrane. ■ Each member of the large family of olfactory receptor proteins is expressed in a small number of olfactory receptors. All neurons expressing a particular receptor protein project to a single glomerulus in the olfactory bulb. ■ Amino acids, sugars, and bitter compounds bind to G protein–coupled receptors in taste sensory cells. ■ Salt and protons (sour) act directly on ion channels to generate receptor potentials in taste cells. ■ Pain and temperature sensations are mediated by a variety of chemical messengers. Direct mechanical damage or excessive heat initiate action potentials in pain fibers. Compounds released from damaged tissue, such as bradykinin, sensitize nociceptive endings. ©2011 Sinauer Associates, Inc. This material cannot be copied, reproduced, manufactured or disseminated in any form without express written permission from the publisher.