α9-nicotinic acetylcholine receptors contribute to the maintenance of chronic mechanical hyperalgesia, but not thermal or mechanical allodynia

BACKGROUND: The current pharmacological treatments for chronic pain are limited. The first analgesic drug approved for clinical use in decades that has a novel molecular target is the synthetic version of a naturally occurring conotoxin. Several conotoxins that target ion channels have progressed to clinical trials for the relief of pain. Vc1.1 and RgIA are analgesic α-conotoxins that target α9-subunit-containing nicotinic acetylcholine receptors (α9-nAChR) as well as GABA(B) receptor mechanisms. However, the evidence for the involvement of α9-nAChRs in pain is controversial. In the present study, the role of the α9-nAChR in pain was assessed using a battery of behavioural pain tests and pain models in α9-nAChR knockout (KO) mice. RESULTS: α9-nAChR KO mice showed normal responses to acute noxious thermal and mechanical stimuli, and developed normal chronic cold and mechanical allodynia in inflammatory and nerve injury pain models. However, KO animals developed mechanical hyperalgesia to a lesser extent than their wild type (WT) counterparts in both inflammatory and neuropathic pain models. Chronic neuropathic pain is sustained in WT mice for at least 21 days post injury, while KO mice show significant recovery by 14 days post injury. KO sham mice were also resistant to the repeated-measures effect of the noxious pain test that caused a gradual onset of mild mechanical hyperalgesia in WT sham animals. CONCLUSIONS: The α9-nAChR is not involved in acute pain perception or chronic thermal or mechanical allodynia or thermal hyperalgesia but does contribute to the intensity and duration of chronic mechanical hyperalgesia, suggesting that pain-relieving actions of antagonists that target this site may be restricted to high threshold mechanosensation. The α9-nAChR appears to be a valid target for pharmacological compounds that alleviate long-term mechanical hyperalgesia and may be of use as a prophylactic drug to prevent the development of some symptoms of chronic pain.