α9-containing nicotinic acetylcholine receptors and the modulation of pain.

Neuropathic pain is a complex and debilitating syndrome for which there are few effective pharmacological treatments. Opioid-based medications are initially effective for acute pain, but tolerance to their analgesic effects quickly develops, and long-term use often leads to physical dependence and addiction. Furthermore, neuropathic pain is generally resistant to non-steroidal anti-inflammatory drugs. Other classes of medications including antidepressants, antiepileptics and voltage-gated calcium channel inhibitors are only partially effective in most patients, may be associated with significant side effects and have few disease-modifying effects on the underlying pathology. Medications that act through new mechanisms of action, and particularly ones that have disease-modifying properties, would be highly desirable. In the last decade, a potential new target for the treatment of neuropathic pain has emerged: the α9-containing nicotinic acetylcholine receptor (nAChR). Recent studies indicate that antagonists of α9-containing nAChRs are analgesic in animal models of neuropathic pain. These nerve injury models include chronic constriction injury, partial sciatic nerve ligation, streptozotocin-induced diabetic neuropathy and chemotherapeutic-induced neuropathy. This review details the history and state of the field regarding the role that α9-containing nAChRs may play in neuropathic pain. An alternative hypothesis that α-conotoxins exert their therapeutic effect through blocking N-type calcium channels via activation of GABAB receptors is also reviewed. Understanding how antagonists of α9-containing nAChRs exert their therapeutic effects may ultimately result in the development of medications that not only treat but also prevent the development of neuropathic pain states. LINKED ARTICLES: This article is part of a themed section on Nicotinic Acetylcholine Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.11/issuetoc.