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

Klimis, H, Adams, DJ, Callaghan, B, Nevin, S, Alewood, P, Vaughan, C, Mozar, C and Christie, M 2011, 'A novel mechanism of inhibition of high-voltage activated calcium channels by a-conotoxins contributes to relief of nerve injury-induced neuropathic pain', Pain, vol. 152, no. 2, pp. 259-266.


Document type: Journal Article
Collection: Journal Articles

Title A novel mechanism of inhibition of high-voltage activated calcium channels by a-conotoxins contributes to relief of nerve injury-induced neuropathic pain
Author(s) Klimis, H
Adams, DJ
Callaghan, B
Nevin, S
Alewood, P
Vaughan, C
Mozar, C
Christie, M
Year 2011
Journal name Pain
Volume number 152
Issue number 2
Start page 259
End page 266
Total pages 8
Publisher Elsevier BV
Abstract a-Conotoxins that are thought to act as antagonists of nicotinic acetylcholine receptors (nAChRs) containing a3-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 a-conotoxins might be mediated by either a9a10 nAChRs or a novel GABAB receptor-mediated inhibition of N-type calcium channels. Here we establish that three a-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 a9a10 nAChRs and GABAB/Ca2+ channels but weakly blocks a3ß2 and a3ß4 nAChRs, produced potent, long-lasting reversal of allodynia that were prevented by pre-treatment with the GABAB receptor antagonist, SCH50911. a-Conotoxin AuIB, a weak a3ß4 nAChR antagonist, inhibited GABAB/Ca2+ channels but did not act on a9a10 nAChRs. AuIB also produced reversal of allodynia. These findings suggest that GABAB receptor-dependent inhibition of N-type Ca2+ channels can mediate the sustained anti-allodynic actions of some a-conotoxins. However, MII, a potent a3ß2 nAChR antagonist but inactive on a9a10 and a3ß4 nAChRs and GABAB/Ca2+ channels, was demonstrated to have short-acting anti-allodynic action. This suggests that a3ß2 nAChRs may also contribute to reversal of allodynia. Together, these findings suggest that inhibition of a9a10 nAChR is neither necessary nor sufficient for relief of allodynia and establish that a-conotoxins selective for GABAB receptor-dependent inhibition of N-type Ca2+ channels relieve allodynia, and could therefore be developed to manage chronic pain.
Subject Basic Pharmacology
Keyword(s) Conotoxin
GABAB receptor
Nicotinic acetylcholine receptor
N-type Ca2+ channel
Sensory neuron
Mechanical allodynia
Neuropathic pain
DOI - identifier 10.1016/j.pain.2010.09.007
Copyright notice © 2010 International Association for the Study of Pain Published by Elsevier B.V.
ISSN 0304-3959
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