TRPM8

TRPM8 is a cold- and menthol-gated, calcium-permeable ion channel that functions as a primary molecular sensor for cold and menthol in humans and supports cold detection in mammalian sensory neurons^[1][2]. Mechanistically, ligand-bound TRPM8 structures identify binding sites for cooling agonists and PI(4,5)P₂, indicating that lipid-dependent allosteric control contributes to TRPM8 activation^[2]. In mouse models, functional TRPM8 channels are required for innocuous cool responses, noxious cold responses, injury-evoked cold hypersensitivity, cooling-mediated analgesia, and thermoregulation^[1]. In disease-relevant models, systemic TRPM8 blockade reduced cold hypersensitivity in inflammatory and nerve-injury pain models, whereas TRPM8 activation by menthol or WS-12 attenuated paclitaxel-induced mechanical pain in rat dorsal root ganglion studies^[1][3]. Compared with related isoforms, TRPM8 differs from TRPV1, a heat/capsaicin receptor, and TRPA1, whose role as a direct noxious cold sensor remains controversial; TRPA1 can instead act upstream of GFRα3 and TRPM8 during neurogenic inflammation-driven cold hypersensitivity^[4]. For experimental applications, selective antagonists such as PBMC and biphenyl amide analogues, and agonists such as menthol and WS-12, provide tools for testing TRPM8 gating, cold allodynia, sensory neuropathy, and analgesic mechanisms^[1][3][5].