Neurobiology of TRPM channels in pain processing: Current advances and future directions.

Chronic pain affects 7-10 % of the global population and remains a major clinical and socioeconomic burden. Transient receptor potential melastatin (TRPM) channels are emerging as key modulators of somatosensory processing and pain pathophysiology. This review examines the roles of major TRPM subtypes including TRPM2, TRPM3, TRPM7, and TRPM8 in diverse chronic pain states. TRPM2 is strongly associated with oxidative stress-driven neuroinflammation and migraine-related mechanisms. TRPM3 contributes to heat sensitivity, inflammatory pain, and spontaneous nociception. TRPM7 regulates calcium and magnesium signaling and has been implicated in neuropathic pain and spinal cord injury-induced hypersensitivity. TRPM8, activated by cooling stimuli, is involved in cold allodynia and aberrant cold sensitivity. Despite preclinical progress with TRPM-targeted therapies, challenges persist, including the need for selective modulators, addressing off-target effects, and understanding overlapping channel functions. Future research must explore combined or multi-targeted approaches and integrate precision medicine to overcome these barriers. By providing insights into TRPM channel mechanisms, this review underscores their potential to transform chronic pain management and pave the way for more effective and targeted treatments.