Download Pain and Temperature Sensation in Skin

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
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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
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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.