A novel mechanism of inhibition of high-voltage activated calcium channels by α-conotoxins contributes to relief of nerve injury-induced neuropathic pain.
α-Conotoxins that are thought to act as antagonists of nicotinic acetylcholine receptors (nAChRs) containing α3-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 α-conotoxins might be mediated by either α9α10 nAChRs or a novel GABA(B) receptor-mediated inhibition of N-type calcium channels. Here we establish that three α-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 α9α10 nAChRs and GABA(B)/Ca(2+) channels but weakly blocks α3β2 and α3β4 nAChRs, produced potent, long-lasting reversal of allodynia that were prevented by pre-treatment with the GABA(B) receptor antagonist, SCH50911. α-Conotoxin AuIB, a weak α3β4 nAChR antagonist, inhibited GABA(B)/Ca(2+) channels but did not act on α9α10 nAChRs. AuIB also produced reversal of allodynia. These findings suggest that GABA(B) receptor-dependent inhibition of N-type Ca(2+) channels can mediate the sustained anti-allodynic actions of some α-conotoxins. However, MII, a potent α3β2 nAChR antagonist but inactive on α9α10 and α3β4 nAChRs and GABA(B)/Ca(2+) channels, was demonstrated to have short-acting anti-allodynic action. This suggests that α3β2 nAChRs may also contribute to reversal of allodynia. Together, these findings suggest that inhibition of α9α10 nAChR is neither necessary nor sufficient for relief of allodynia and establish that α-conotoxins selective for GABA(B) receptor-dependent inhibition of N-type Ca(2+) channels relieve allodynia, and could therefore be developed to manage chronic pain.
Klimis
Harry
H
Pain Management Research Institute, University of Sydney, Royal North Shore Hospital, St. Leonards NSW 2065, Australia Brain and Mind Research Institute, University of Sydney, NSW 2006, Australia Queensland Brain Institute, The University of Queensland, Brisbane, Queensland 4072, Australia Health Innovations Research Institute, RMIT University, Melbourne, Victoria 3083, Australia Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia.
Adams
D J
DJ
Callaghan
B
B
Nevin
S
S
Alewood
P F
PF
Vaughan
C W
CW
Mozar
C A
CA
Christie
M J
MJ
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology* / Q000627:therapeutic use; D020864:Calcium Channels, N-Type / Q000378:metabolism* / Q000502:physiology; D002478:Cells, Cultured; D020916:Conotoxins / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D005260:Female; D008297:Male; D010146:Pain / Q000209:etiology / Q000378:metabolism* / Q000517:prevention & control*; D010523:Peripheral Nervous System Diseases / Q000150:complications* / Q000188:drug therapy* / Q000378:metabolism*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D020426:Sciatic Neuropathy / Q000150:complications / Q000378:metabolism; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
D002121:Calcium Channel Blockers; D020864:Calcium Channels, N-Type; D020916:Conotoxins