|Recommended name:||Transient receptor potential cation channel subfamily M member 8|
|Sequence length:||1104 AA.|
The mechanism of cold-induced analgesia was unclear until the discovery of the transient receptor potential cation channel subfamily M member 8 (TRPM8). TRPM8 is also known as the cold and menthol receptor.
While the 3D structure remains unknown, it is clear that the protein is 1104 amino acids long. It has six transmembrane domains, four of them identical and a pore P-loop between the fifth and the sixth domains. Both ends are located intracellularly. It is a non-selective cation channel, allowing the entry of Na+ and Ca2+ to the cell. TRPM8 is activated by cold temperatures (<25°C) and cooling agents, such as menthol or icilin. Cooling and compounds such as menthol shift the activation curve of TRPM8 to lower potentials, which leads to an increased probability of channel opening.
Acidic conditions inhibit the Ca2+ response to menthol and icilin. There are to mechanisms for ligands. While antagonists physically block the receptor for cold and menthol, agonists activate TRPM8 and produce a cooling sensation.
Orofacial pain is often associated with the affection of sensory branches of the trigeminal nerve. Pain can occur before and after endodontic treatment, TMJ disorders, sinusitis, neuralgia, neuropathic pain etc. Many of these conditions are associated with cold hypersensitivity. TRPM8 channels are present in trigeminal neurons, but their role in trigeminal cold pain is unknown at present.
Dentine sensitivity due to an exposure of dentin is a very common pain sensation. The prevalence of reported sensitivity in adults is about 60%. Reasons can be erosions resulting from acidic beverages and food, or abrasion resulting from intense tooth brushing, or gingival retraction resulting from periodontitis. Cold temperatures commonly trigger pain, but the mechanism of cold detection of teeth is still unclear. Recent studies indicate that the nociceptors in the dentin-pulp border area are activated by hydrodynamic fluid flow. The flow stimulates the nerve endings and causes their activation. Other theories are direct activation of trigeminal afferents and responses mediated by odontoblasts. Studies revealed that TRPV1, TRPA1 and TRPM8 and Nav1.8 are expressed by human odontoblasts. Patients with teeth diagnosed an irreversible pulpitis suffer from cold hyperalgesia. This hyperalgesia may be a result of reduced TRPM8 labelling in axonal areas.
Migraine is a neurological disorder characterizes by severe headaches with symptoms like nausea and sensitivity to light and sound. A TRPM8 gene variant was found to be associated with migraine in women, but the pathophysiology is unclear to date.
Dry eye disease is common problem in the aging society but also in younger people wearing contact lenses. A topical application of menthol on the eye surface produces a sensation of freshness. Mechanisms involved in dry eye disease are uncertain, but TRPM8 agonists open new possibilities for the treatment of dry eyes and other mucosal surfaces.