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Toxins 2015, 7(10), 3916-3932;

Conotoxin Interactions with α9α10-nAChRs: Is the α9α10-Nicotinic Acetylcholine Receptor an Important Therapeutic Target for Pain Management?

Discipline of Pharmacology, the University of Sydney, Sydney, NSW 2006, Australia
Author to whom correspondence should be addressed.
Academic Editor: Irina Vetter
Received: 17 August 2015 / Revised: 14 September 2015 / Accepted: 18 September 2015 / Published: 28 September 2015
(This article belongs to the Special Issue Conotoxins: Novel Pharmacologies for Nervous System Disorders)
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The α9α10-nicotinic acetylcholine receptor (nAChR) has been implicated in pain and has been proposed to be a novel target for analgesics. However, the evidence to support the involvement of the α9α10-nAChR in pain is conflicted. This receptor was first implicated in pain with the characterisation of conotoxin Vc1.1, which is highly selective for α9α10-nAChRs and is an efficacious analgesic in chronic pain models with restorative capacities and no reported side effects. Numerous other analgesic conotoxin and non-conotoxin molecules have been subsequently characterised that also inhibit α9α10-nAChRs. However, there is evidence that α9α10-nAChR inhibition is neither necessary nor sufficient for analgesia. α9α10-nAChR-inhibiting analogues of Vc1.1 have no analgesic effects. Genetically-modified α9-nAChR knockout mice have a phenotype that is markedly different from the analgesic profile of Vc1.1 and similar conotoxins, suggesting that the conotoxin effects are largely independent of α9α10-nAChRs. Furthermore, an alternative mechanism of analgesia by Vc1.1 and other similar conotoxins involving non-canonical coupling of GABAB receptors to voltage-gated calcium channels is known. Additional incongruities regarding α9α10-nAChRs in analgesia are discussed. A more comprehensive characterisation of the role of α9α10-nAChRs in pain is crucial for understanding the analgesic action of conotoxins and for improved drug design. View Full-Text
Keywords: α-conotoxins; α9α10-nicotinic acetylcholine receptors; pain α-conotoxins; α9α10-nicotinic acetylcholine receptors; pain

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Mohammadi, S.A.; Christie, M.J. Conotoxin Interactions with α9α10-nAChRs: Is the α9α10-Nicotinic Acetylcholine Receptor an Important Therapeutic Target for Pain Management? Toxins 2015, 7, 3916-3932.

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