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

Klimis, Harry, Adams, D. J., Callaghan, B., Nevin, S., Alewood, P. F., Vaughan, C. W., Mozar, C. A. and Christie, M. J. (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, 152 2: 259-266. doi:10.1016/j.pain.2010.09.007


Author Klimis, Harry
Adams, D. J.
Callaghan, B.
Nevin, S.
Alewood, P. F.
Vaughan, C. W.
Mozar, C. A.
Christie, M. J.
Title A novel mechanism of inhibition of high-voltage activated calcium channels by a-conotoxins contributes to relief of nerve injury-induced neuropathic pain
Formatted title
A novel mechanism of inhibition of high-voltage activated calcium channels by α-conotoxins contributes to relief of nerve injury-induced neuropathic pain
Journal name Pain   Check publisher's open access policy
ISSN 0304-3959
1872-6623
0167-6482
Publication date 2011-02
Year available 2010
Sub-type Article (original research)
DOI 10.1016/j.pain.2010.09.007
Volume 152
Issue 2
Start page 259
End page 266
Total pages 8
Editor Allan I. Basbaum
Place of publication Amsterdam, Netherlands
Publisher Elsevier/North-Holland
Collection year 2011
Language eng
Formatted abstract
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 GABAB 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 GABAB/Ca2+ channels but weakly blocks α3β2 and α3β4 nAChRs, produced potent, long-lasting reversal of allodynia that were prevented by pre-treatment with the GABAB receptor antagonist, SCH50911. α-Conotoxin AuIB, a weak α3β4 nAChR antagonist, inhibited GABAB/Ca2+ channels but did not act on α9α10 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 α-conotoxins. However, MII, a potent α3β2 nAChR antagonist but inactive on α9α10 and α3β4 nAChRs and GABAB/Ca2+ 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 GABAB receptor-dependent inhibition of N-type Ca2+ channels relieve allodynia, and could therefore be developed to manage chronic pain.
© 2010 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
Keyword Conotoxin
GABAB receptor
Mechanical allodynia
N-type Ca2 + channel
Neuropathic pain
Nicotinic acetylcholine receptor
Sensory neuron
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Available online 28 September, 2010.

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2011 Collection
Queensland Brain Institute Publications
Institute for Molecular Bioscience - Publications
 
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Created: Fri, 10 Dec 2010, 10:41:32 EST by Debra McMurtrie on behalf of Queensland Brain Institute