Neuronal nicotinic acetylcholine receptor ligands as potential analgesics

Neuronal nicotinic acetylcholine receptors (nAChRs) are ligand-gated cation channels that mediate fast responses of neurons to the neurotransmitter acetylcholine (ACh). Although related to muscle nAChRs, neuronal nAChRs display a different pharmacology. Neuronal nAChR-mediated analgesia is observed in rodent pain models but activation of nAChRs can also produce undesirable effects, many related to autonomic function. However, nAChR subtype diversity provides the opportunity to develop selective agents with improved safety margins, with the alpha4beta2 nAChR subtype important in attenuating acute thermal pain and the alpha3beta4 subtype critical for autonomic function. Recent evidence that alpha7 nAChRs are involved in pain and inflammation is exciting but requires validation. Recent patent literature reveals increased interest in nAChR ligands for pain, as well as other therapeutic indications. New structure types are being developed, with new alpha7 ligands being particularly noteworthy but the minimal disclosure of biological data in many recent patents makes evaluation of their utility difficult.