The transient receptor potential (TRP) channels, TRPV1, TRPA1, and TRPM8 in particular, are chief molecular sensors for pain and chronic pain signal detection. As polymodal cation channels, they locally detect thermal, chemical, and mechanical stimuli in sensory neurons and hence contribute to nociceptive, nociplastic, and neuropathic pain conditions such as arthritis, diabetic neuropathy, and migraines. When dysregulated, they become linked to disorders like overactive bladder, cancer, and inflammation. TRPV1 is heat and capsaicin receptor that integrate painful stimuli and initiate neurogenic inflammation; resiniferatoxin, a TRPV1 agonist, is currently on trial for cancer pain, whereas, TRPV1 antagonists (e.g., NEO6860, mavatrep) often fail due to hyperthermia, burns, or less efficacy. TRPA1 reacts to irritants and oxidative stress while its antagonist, GRC-17536, is effective in phase II diabetic neuropathy studies but discontinued due to pharmacokinetic liabilities. TRPM8 is a cold sensor and a potential migraine target; antagonist like PF-05105679 reduce cold pain but cause mild side effects, whereas, agonists are useful for dry eye. Among the problems which have delayed clinical translation are species differences, poor pharmacokinetics, as well as on-target toxicities. Through their modulation, it is possible to achieve a therapeutic breakthrough in pain conditions that are currently not adequately treated. Efforts are being made in creating thermoneutral antagonists, siRNAs, and novel derivatives.
Choudhary et al. (2026) studied this question.