Nicotinic acetylcholine receptors in pain modulation

Chronic pain is widely recognized as a major global health problem that affects approximately one-fifth of the adult population and is associated with significant physical, psychological, and socioeconomic burden. Current clinical analgesic strategies are mainly based on non-steroidal anti-inflammatory drugs, opioids, and adjuvant agents including antidepressants and antiepileptic drugs. However, these therapies are limited by insufficient efficacy in neuropathic pain, considerable adverse effects, and the risks of tolerance and addiction. Therefore, the development of safer and more effective non-opioid analgesics remains an important unmet clinical need. Nicotinic acetylcholine receptors (nAChRs) have been identified as promising targets for the development of next-generation analgesics because of their roles in pain signal transmission, neuroinflammation, and immune-neural interactions. nAChRs are pentameric ligand-gated ion channels composed of different subunit combinations, which give rise to multiple receptor subtypes with distinct expression patterns and functional properties. Increasing evidence suggests that specific nAChR subtypes, including α3β4, α4β2, α6β4, α9α10, and α7, participate in the regulation of inflammatory pain, neuropathic pain, and cancer-related pain. This review summarizes recent progress in the understanding of subtype-specific roles of nAChRs in pain regulation. The development of highly selective tool compounds, particularly α-conotoxin-derived peptides, is discussed together with current knowledge regarding the mechanisms associated with nAChR-mediated analgesia. Challenges related to clinical translation and potential therapeutic strategies are also considered.