33.5 Touch Includes the Sensing of Pressure, Temperature, and Other Factors

Like taste, touch is a combination of sensory systems that are expressed in a common organ—in this case, the skin. The detection of pressure and the detection of temperature are two key components. Amiloride-sensitive Na+ channels, homologous to those of taste, appear to play a role. Other systems are responsible for detecting painful stimuli such as high temperature, acid, or certain specific chemicals. Although our understanding of this sensory system is not as advanced as that of the others, recent work has revealed a fascinating relation between pain and taste sensation, a relation well known to anyone who has eaten “spicy” food.

Studies of capsaicin reveal a receptor for sensing high temperatures and other painful stimuli

Our sense of touch is intimately connected with the sensation of pain. Specialized neurons, termed nociceptors, transmit signals from skin to pain-processing centers in the spinal cord and brain in response to the onset of tissue damage. What is the molecular basis for the sensation of pain? An intriguing clue came from the realization that capsaicin, the chemical responsible for the “hot” taste of spicy food, activates nociceptors.

Figure 33.35: The membrane topology deduced for VR1, the capsaicin receptor. The proposed site of the membrane pore is indicated in red, and the three ankyrin (A) repeats are shown in orange. The active receptor comprises four of these subunits.
[Information from M. J. Caterina et al., Nature 389:816–824, 1997.]

Early research suggested that capsaicin would act by opening ion channels that are expressed in nociceptors. Thus, a cell that expresses the capsaicin receptor should take up calcium on treatment with the molecule. This insight led to the isolation of the capsaicin receptor with the use of cDNA from cells expressing this receptor. Such cells had been detected by their fluorescence when loaded with the calcium-sensitive compound Fura-2 and then treated with capsaicin or related molecules. Cells expressing the capsaicin receptor, which is called VR1 (for vanilloid receptor 1), respond to capsaicin below a concentration of 1 μM. The deduced 838-residue sequence of VR1 revealed it to be a member of the TRP channel family (Figure 33.35). The amino-terminal region of VR1 includes three ankyrin repeats.

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Currents through VR1 are also induced by temperatures above 40°C and by exposure to dilute acid, with a midpoint for activation at pH 5.4 (Figure 33.36). Temperatures and acidity in these ranges are associated with infection and cell injury. The responses to capsaicin, temperature, and acidity are not independent. The response to heat is greater at lower pH, for example. Thus, VR1 acts to integrate several noxious stimuli. We feel these responses as pain and act to prevent the potentially destructive conditions that cause the unpleasant sensation. Studies of mice that do not express VR1 suggest that this is the case; such mice do not mind food containing high concentrations of capsaicin and are, indeed, less responsive than control mice to normally noxious heat. Plants such as chili peppers presumably gained the ability to synthesize capsaicin and other “hot” compounds to protect themselves from being consumed by mammals. Birds, which play the beneficial role of spreading pepper seeds into new territory, do not appear to respond to capsaicin.

Figure 33.36: Response of the capsaicin receptor to pH and temperature. The ability of this receptor to respond to acid and to increased temperature helps detect potentially noxious situations.
[Data from M. Tominaga et al., Neuron 21:531–543, 1998.]

Because of its ability to simulate VR1, capsaicin is used in pain management for arthritis, neuralgia, and other neuropathies. How can a compound that induces pain assist in its alleviation? Chronic exposure to capsaicin overstimulates pain-transmitting neurons, leading to their desensitization.