The involvement of α9α10-nicotinic acetylcholine receptors in pain states

Abstract

The α9 subunit of nicotinic acetylcholine receptors (α9-nAChR) has recently attracted the interest of pain researchers, after the discovery of highly efficacious α9α10-nAChR-inhibiting analgesics. The α9α10-nAChR has since been pursued as a novel analgesic target. However, the evidence to implicate this receptor subunit in nociception and analgesia has been indirect and conflicted. Here, a direct approach to studying the role of the α9α10-nAChR in pain and other behavioural states was undertaken. Pain phenotyping in α9-nAChR knockout (KO) mice revealed a limited clinical potential for specific α9-nAChR-inhibitors, with only one pain modality (mechanical hyperalgesia) affected by this receptor deletion. Histological analyses showed that the mechanism of action of known α9α10-nAChR-inhibiting analgesics might be independent of their α9α10-nAChR-inhibiting properties While no side effects of α9-nAChR-inhibiting analgesics have been reported, behavioural phenotyping of α9-nAChR KO mice revealed a susceptibility of this genotype to stress-induced dysregulation of behavioural and physiological affective responses, which is likely hypothalamic-pituitary-adrenal (HPA)-axis mediated. The results have expanded on our understanding of the role of α9α10-nAChRs in pain. α9α10-nAChRs were found to have a limited role in the development and maintenance of chronic pain, indicating that the clinical application for specific α9α10-nAChR-inhibiting analgesics would be narrow. Furthermore, the potential for unforseen negative side effects was uncovered.