desensitization properties, was used as a control for nicotine, to distinguish it from menthol-induced response. The menthol receptor was seen to sensitize or desensitize based on cellular conditions, and menthol produces increased activity in Ca2+-voltage gated channels that is not seen in ethanol, cyclohexanol and other irritant controls, suggestive of a specific molecular receptor. Dessirier et al., 2001, also claim the cross-desensitization of menthol receptors can occur by unknown molecular mechanisms, though they hypothesize the importance of Ca2+ in reducing cell excitability in a way similar to that in the capsaicin receptor. Mutagenesis of protein kinase C phosphorylation sites in TRPM8 (wild type serines and threonines replaced by alanine in mutants) reduces the desensitizing response. Caryophyllene inhibits TRPM8, which helps mammals to improve cold tolerance at low ambient temperatures. Cross-desensitization Cliff et al., 1994, performed a study to discover more about the properties of the menthol receptor and whether menthol had the ability to cross-desensitize with other chemical irritant receptors. Capsaicin was known to cross-desensitize with other irritant agonists, where the same information was not known about menthol. The study involved subjects swishing either menthol or capsaicin for an extended time at regular intervals. There were three significant conclusions about cross-desensitizing: 1) Both chemicals self-desensitize, 2) menthol receptors can desensitize in response to capsaicin, and, most novelly, 3) capsaicin receptors are sensitized in response to menthol. Ligands Agonists In a search for compounds that activated the TRPM8 cold receptor, compounds that produce a cooling-sensation were sought out from the fragrance industries. Of 70 relevant compounds, the following 10 produced the associated [Ca2+]-increase response in mTRPM8-transfected HEK293 cells used to identify agonists. Experimentally identified and commonly utilized agonists of the menthol receptor include linalool, geraniol, hydroxy-citronellal, icilin, WS-12, Frescolat MGA, Frescolat ML, PMD 38, Coolact P, M8-Ag and Cooling Agent 10. Traditionally used agonists include menthol and borneol. Antagonists BCTC, thio-BCTC, capsazepine and M8-An were identified as antagonists of the TRPM8 receptor. These antagonists physically block the receptor for cold and menthol, by binding to the S1-S4 voltage-sensing domain, preventing response. AMG-333 RQ-00434739 RQ-00203078 PF-05105679 cas: [1398583-31-7]. M8 B AMTB 5-benzyloxytryptamine Anandamide N-Arachidonoyl dopamine Tetrahydrocannabinol Tetrahydrocannabinolic acid Cannabidiol Cannabidiolic acid Cannabigerol Tetrahydrocannabivarin Tetrahydrocannabivarin Acid Cannabidivarin Cannabigerolic acid Cannabigerovarin Cannabichromene Cannabinol Clinical significance Cold-patches have traditionally been used to induce analgesia or relief in pain which is caused as result of traumatic injuries. The underlying mechanism of cold-induced analgesia remained obscure until