TRPM8

TRP M8 (TRPM8 is the acronym for "transient receptor potential melastin 8"). This is an ion channel that is permeable for monovalent cations and for Ca2+ as well as for Mg2+. TRPM8, like other TRP ion channels, is characterized by the fact that it has 6 transmembrane regions. The channel is activated by chemical cooling agents (e.g. menthol and menthol derivatives such as menthoxypropanediol). Furthermore, it is activated when the outside temperature drops below 26°C. See also capsaicin receptor. Sensory nerve fibers perceive temperature shifts over a relatively wide range.

This process is thought to occur via direct "activation of heat-sensitive" excitatory TRP (transient receptor potential) ion channels.The ion channel is thought to transmit the sensation of cold stimuli predominantly via afferent sensory neurons. TRPM8 deficient mice exhibited marked behavioral deficits in the discrimination of warm and cold surfaces. These results suggest an essential role of TRPM8 in cold sensation and confirm the hypothesis that TRP channels are the main sensors of temperature stimuli in the peripheral nervous system.

Furthermore, there is evidence that activation of the TRPM8 receptor inhibits UV-induced inflammatory activities.

TRP channelopathies are caused by mutations in genes that code for TRP channels. Several hereditary diseases in humans (so-called "TRP channelopathies") that affect the cardiovascular, renal, skeletal and nervous systems are summarized under this term (Nilius B et al. 2011). TRP channels are also promising targets for drug development. For example, a number of potent small molecule TRPV1 channel antagonists (occasionally also TRPM8 antagonists) are now showing therapeutic benefit in the treatment of inflammatory and neuropathic pain (Moran MM et al. 2018).

There is evidence of a link between sensitivity to cold pain and the rs12992084 polymorphism of the TRPM8 gene. Furthermore, there is a correlation between sensitivity to cold and the rs2243057 of the PAR2/F2RL1 gene. It can be assumed that genetic polymorphisms of both PAR2/F2RL1 and TRPM8 are involved in the individual differences in sensitivity to cold pain (Soeda M et al. 2021)

There is evidence that the carcinogenesis of various tumors (colon carcinoma) is inhibited by TRPM8 antagonists (cannabigerol).

In a randomized double-blind study on 70 patients, it was shown that a combination of two agonists of the TRPM8 receptors (CHC and menthoxypropanediol - MPD) in an external agent led to a significant reduction in itching (Ständer S et l. 2017). Side effects: sensation of cold and burning.

1. Borrelli Fet al.(2014) Colon carcinogenesis is inhibited by the TRPM8 antagonist cannabigerol, a Cannabis-derived non-psychotropic cannabinoid. Carcinogenesis. PubMed PMID: 25269802.
2. Morgan K et al. (2014) Human TRPM8 and TRPA1 pain channels, including a gene variant with increased sensitivity to agonists (TRPA1 R797T), exhibit differential regulation by SRC-tyrosine kinase inhibitor. Biosci Rep 34i: e00131
3. Moran MM et al. (2018) Targeting nociceptive transient receptor potential channels to treat chronic pain: current state of the field. Br J Pharmacol 175:2185-2203.
4. Nilius B et al. (2011) The transient receptor potential family of ion channels. Genome Biol 12:218.
5. Park NH et al. (2013) Activation of transient receptor potential melastatin 8 reduces ultraviolet B-induced prostaglandin E2 production in keratinocytes. J Dermatol 40:919-922
6. Soeda M et al. (2021) Cold pain sensitivity is associated with single-nucleotide polymorphisms of PAR2/F2RL1 and TRPM8. Mol Pain 17:17448069211002009.
7. Ständer S et al. (2017) Novel TRPM8 agonist cooling compound against chronic itch: results from a randomized, double-blind, controlled, pilot study in dry skin.J Eur Acad Dermatol Venereol 31:1064-1068.
8. Wang Y et al. (2017) Targeting Transient Receptor Potential Canonical Channels for Diseases of the Nervous System. Curr Drug Targets.18:1460-1465.
9. Winchester WJet al. (2014) Inhibition of TRPM8 channels reduces pain in the cold pressor test in humans. J Pharmacol Exp Ther 351:259-269