agonists of the TRPM8 receptor. It works in conjunction with the TRPV1 receptor to maintain a feasible threshold temperature range in which our cells are comfortable and our perception of these stimuli occurs at the spinal cord and brain, which integrate signals from different fibers of varying sensitivity to temperature. Application of menthol to skin or mucus membranes results directly in membrane depolarization, followed by calcium influx via voltage-dependent calcium channels, providing evidence for the role of TRPM8 and other TRP receptors to mediate our sensory interaction with the environment in response to cold in the same way as in response to menthol. Properties pH-sensitivity In contrast to the TRPV1 (capsaicin) receptor, which is potentiated by low pH, acidic conditions were shown to inhibit the TRPM8 Ca2+ response to menthol and icilin (an agonist of the menthol receptor). It is hypothesized the TRPV1 and TRPM8 receptors act together in response to inflammatory conditions: TRPV1, by proton action, increases the burning sensation of pain, while the acidity inhibits TRPM8 to block the more pleasant sensation of coolness in more dire instances of pain. Sensitization Numerous studies have been published investigating the effect of L-menthol application as a model for TRPM8-sensitization. The primary consensus finding is that TRPM8 sensitization increases the sensation of cold pain, also known as cold hyperalgesia. An experiment was done in a double-blind two-way crossover study by applying 40% L-menthol to the forearm, using ethanol as a control. Activation of the TRPM8-receptor channel (the primary menthol receptor channel) resulted in increased sensitization to the menthol stimulus. To investigate the mechanisms of this sensitization, Wasner et al., 2004, performed A fiber conduction blockade of the superficial radial nerve in another group of subjects. This ended up reducing the menthol-induced sensation of cold and hyperalgesia because blocking A fiber conduction resulted in inhibition of a class of group C nerve fiber nociceptors needed to transduce the sensation of pain. They concluded menthol sensitizes cold-sensitive peripheral C nociceptors and activates cold-specific A delta fibers. Desensitization As is common in response to many other sensory stimuli, much experimental evidence exists for the desensitization of human response of TRPM8 receptors to menthol. Testing involving administration of menthol and nicotine-containing cigarettes non-smokers, which induced what they classified as an irritant response, after initial sensitization, showed a declining response in subjects over time, lending itself to the incidence of desensitization. Ethanol, with similar irritant and