the discovery of TRPM8. One research group has reported that TRPM8 is activated by chemical cooling agents (such as menthol) or when ambient temperatures drop below approximately 26 °C, suggesting that it mediates the detection of cold thermal stimuli by primary afferent sensory neurons of afferent nerve fibers. Three independent research groups have reported that mice lacking functional TRPM8 gene expression are severely impaired in their ability to detect cold temperatures. Remarkably, these animals are deficient in many diverse aspects of cold signaling, including cool and noxious cold perception, injury-evoked sensitization to cold, and cooling-induced analgesia. These animals provide a great deal of insight into the molecular signaling pathways that participate in the detection of cold and painful stimuli. Many research groups, both in universities and pharmaceutical companies, are now actively involved in looking for selective TRPM8 ligands to be used as new generation of neuropathic analgesic drugs. Low concentrations of TRPM8 agonists such as menthol (or icilin) found to be antihyperalgesic in certain conditions, whereas high concentrations of menthol caused both cold and mechanical hyperalgesia in healthy volunteers. TRPM8 knockout mice not only indicated that TRPM8 is required for cold sensation but also revealed that TRPM8 mediates both cold and mechanical allodynia in rodent models of neuropathic pain. Furthermore, recently it was shown that TRPM8 antagonists are effective in reversing established pain in neuropathic and visceral pain models. TRPM8 upregulation in bladder tissues correlates with pain in patients with painful bladder syndromes. Furthermore, TRPM8 is upregulated in many prostate cancer cell lines and Dendreon/Genentech are pursuing an agonist approach to induce apoptosis and prostate cancer cell death. Role in cancer TRPM8 channels may be a target for treating prostate cancer. TRPM8 is an androgen dependent Ca2+ channel necessary for prostate cancer cells to survive and grow. Immunofluorescence showed expression of the TRPM8 protein in the ER and plasma membrane of the androgen-responsive LNCaP cell line. TRPM8 was expressed in androgen-insensitive cells, but it was not shown to be needed for their survival. By knockout of TRPM8 with siRNAs targeting TRPM8 mRNAs, the necessity of the TRPM8 receptor was shown in the androgen-dependent cancer cells. This has useful implications in terms of gene therapy, as there are so few treatment options for men with prostate cancer. As an androgen-regulated protein whose function is lost as cancer develops in cells, the TRPM8 protein seems to be especially critical in regulating calcium