TRPM8

TRPM8 is an ion channel: upon activation, it allows the entry of Na⁺ and Ca²⁺ ions into the cell, which leads to depolarization and the generation of an action potential. The signal is conducted from primary afferents (type C- and A-delta) eventually leading to the sensation of cold and cold pain.^[5]

The TRPM8 protein is expressed in sensory neurons, and it is activated by cold temperatures and cooling agents, such as menthol and icilin whereas WS-12 and CPS-369 are the most selective agonists of TRPM8.^[11][12]

TRPM8 is also expressed in the prostate, lungs, and bladder where its function is not well understood.

Role in the nervous system

The transient receptor potential channel (TRP) superfamily, which includes the menthol (TRPM8) and capsaicin receptors (TRPV1), serve a variety of functions in the peripheral and central nervous systems. In the peripheral nervous system, TRPs respond to stimuli from temperature, pressure, inflammatory agents, and receptor activation. Central nervous system roles of the receptors include neurite outgrowth, receptor signaling, and excitotoxic cell death resulting from noxious stimuli.^[13]

McKemy et al., 2002 provided some of the first evidence for existence of a cold-activated receptor throughout the mammalian somatosensory system.

In contrast to the TRPV1 (capsaicin) receptor, which is potentiated by low pH, acidic conditions were shown to inhibit the TRPM8 Ca²⁺ response to menthol and icilin (an agonist of the menthol receptor). It is hypothesized the TRPV1 and TRPM8 receptors act together in response to inflammatory conditions: TRPV1, by proton action, increases the burning sensation of pain, while the acidity inhibits TRPM8 to block the more pleasant sensation of coolness in more dire instances of pain.^[15]

Sensitization

Numerous studies have been published investigating the effect of L-menthol application as a model for TRPM8-sensitization.

As is common in response to many other sensory stimuli, much experimental evidence exists for the desensitization of human response of TRPM8 receptors to menthol.[5] Testing involving administration of menthol and nicotine-containing cigarettes non-smokers, which induced what they classified as an irritant response, after initial sensitization, showed a declining response in subjects over time, lending itself to the incidence of desensitization. Ethanol, with similar irritant and 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.^[18]

Mutagenesis of protein kinase C phosphorylation sites in TRPM8 (wild type serines and threonines replaced by alanine in mutants) reduces the desensitizing response.^[19]

Caryophyllene inhibits TRPM8, which helps mammals to improve cold tolerance at low ambient temperatures.^[20]

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.^[21]

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.^[15][16] Traditionally used agonists include menthol^[22] and borneol.^[23]

Antagonists

BCTC,

• AMG-333
• RQ-00434739
• RQ-00203078
• PF-05105679 cas: [1398583-31-7].
• M8 B
• AMTB
• 5-benzyloxytryptamine^[25]
• Anandamide^[26]
• N-Arachidonoyl dopamine^[26]
• Tetrahydrocannabinol^[27]
• Tetrahydrocannabinolic acid^[27]
• Cannabidiol^[27]
• Cannabidiolic acid^[27]
• Cannabigerol^[27]
• Tetrahydrocannabivarin^[28]
• Tetrahydrocannabivarin Acid^[28]
• Cannabidivarin^[28]
• Cannabigerolic acid^[28]
• Cannabigerovarin^[28]
• Cannabichromene^[28]
• Cannabinol^[28]

Clinical significance

Cold-patches have traditionally been used to induce

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.^[30]

Three independent research groups have reported that mice lacking functional TRPM8 gene expression are severely impaired in their ability to detect

Low concentrations of TRPM8 agonists such as menthol (or icilin) found to be antihyperalgesic in certain conditions,[32] whereas high concentrations of menthol caused both cold and mechanical hyperalgesia in healthy volunteers.^[17]

TRPM8

TRPM8 upregulation in bladder tissues correlates with pain in patients with painful bladder syndromes.[35] 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.^[36]

Role in cancer

TRPM8 channels may be a target for treating

• Endocannabinoid system
• TRPM
• Ruthenium red

References