A novel mechanism of inhibition of high-voltage activated calcium channels by α-conotoxins contributes to relief of nerve injury-induced neuropathic pain

alpha-Conotoxins that are thought to act as antagonists of nicotinic acetylcholine receptors (nAChRs) containing alpha 3-subunits are efficacious in several preclinical models of chronic pain. Potent interactions of Vc1.1 with other targets have suggested that the pain-relieving actions of alpha-conotoxins might be mediated by either alpha 9 alpha 10 nAChRs or a novel GABA(B) receptor-mediated inhibition of N-type calcium channels. Here we establish that three alpha-conotoxins, Vc1.1, AuIB and MII have distinct selectivity profiles for these three potential targets. Their potencies after intramuscular administration were then determined for reversal of allodynia produced by partial nerve ligation in rats. Vc1.1, which potently inhibits alpha 9 alpha 10 nAChRs and GABA(B)/Ca2+ channels but weakly blocks alpha 3 beta 2 and alpha 3 beta 4 nAChRs, produced potent, long-lasting reversal of allodynia that were prevented by pre-treatment with the GABA(B) receptor antagonist, SCH50911. alpha-Conotoxin AuIB, a weak alpha 3 beta 4 nAChR antagonist, inhibited GABA(B)/Ca2+ channels but did not act on alpha 9 alpha 10 nAChRs. AuIB also produced reversal of allodynia. These findings suggest that GABA(B) receptor-dependent inhibition of N-type Ca2+ channels can mediate the sustained anti-allodynic actions of some alpha-conotoxins. However, MII, a potent alpha 3 beta 2 nAChR antagonist but inactive on alpha 9 alpha 10 and alpha 3 beta 4 nAChRs and GABA(B)/Ca2+ channels, was demonstrated to have short-acting anti-allodynic action. This suggests that alpha 3 beta 2 nAChRs may also contribute to reversal of allodynia. Together, these findings suggest that inhibition of alpha 9 alpha 10 nAChR is neither necessary nor sufficient for relief of allodynia and establish that alpha-conotoxins selective for GABA(B) receptor-dependent inhibition of N-type Ca2+ channels relieve allodynia, and could therefore be developed to manage chronic pain. (C) 2010 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.