Development of TRPM8 Antagonists to Treat Chronic Pain and Migraine

Abstract

A review. Development of pharmaceutical antagonists of transient receptor potential melastatin 8 (TRPM8) have been pursued for the treatment of chronic pain and migraine. This review focuses on the current state of this progress.

Antinociceptive effect of two novel transient receptor potential melastatin 8 antagonists in acute and chronic pain models in rat

“…Blocking the activity of the channel by the administration of TRPM8 antagonists or by genetic ablation using mice lacking TRPM8, significantly attenuated thermal responses in nerve injury‐induced pain (Knowlton et al, ; Patel et al, ). This evidence suggests that the in vivo antagonism of TRPM8 holds promise for the successful treatment of neuropathic cold hypersensitivity (Marwaha et al, ; Weyer and Letho, ). A key challenge in the discovery of TRPM8 blockers is the identification of highly selective molecules with a good pharmacokinetic profile suitable to provide an efficacious dose response.…”

Targeting nociceptive transient receptor potential channels to treat chronic pain: current state of the field

“…The medicinal chemistry and pharmacology of TRPM8 channels are detailed elsewhere (DeFalco et al, ; Fernández‐Pena and Viana, ; Weyer and Lehto, ). Here, it suffices to mention that, as illustrated in Figure , TRPM8 channels are activated by cooling compounds such as menthol (in peppermint) and the synthetic menthol congeners, icilin (McKemy et al, ; Peier et al, ; Bödding et al, ) and WS‐12 (Sherkheli et al, ).…”

Using a Genetic Risk Score Approach to Predict Headache Response to Triptans in Migraine Without Aura

“…34 The observation of a nominal association between TRPM8 rs6724624 and efficacy of triptan drugs is noteworthy, given the direct involvement of TRPM8 in the pathogenesis of migraine [35][36][37] and the evidence that it could serve as a novel target for migraine treatment. 38 Although the precise role of TRPM8 in migraine pathophysiology remains elusive, the TRPM8 channel is known to form a complex with the 5-HT 1B receptor in primary afferent neurons, which amplifies the analgesic effects of both TRPM8 activators and 5-HT 1B agonists in tissue-and nerve-injury rat models. 39 Although our results raise the possibility that triptan efficacy may be influenced by TRPM8-targeting drugs, further investigation is required to test this hypothesis as well as to tackle the mechanistic insights behind the observed higher response rate of MwoA patients carrying the TRPM8 rs6724624CC genotype.…”