title: Conotoxin Interactions with α9α10-nAChRs: Is the α9α10-Nicotinic Acetylcholine Receptor an Important Therapeutic Target for Pain Management?
abstract: 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.
authors.affiliation: Discipline of Pharmacology, the University of Sydney, Sydney, NSW 2006, Australia. sarasa.mohammadi@sydney.edu.au.
authors.forename: Sarasa A
authors.initials: SA
authors.lastname: Mohammadi
authors.affiliation: Discipline of Pharmacology, the University of Sydney, Sydney, NSW 2006, Australia. mac.christie@sydney.edu.au.
authors.forename: MacDonald J
authors.initials: MJ
authors.lastname: Christie
mesh_terms: D000700:Analgesics / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D020916:Conotoxins / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D006801:Humans; D018345:Mice, Knockout; D018733:Nicotinic Antagonists / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D010146:Pain / Q000188:drug therapy* / Q000378:metabolism*; D051381:Rats; D011978:Receptors, Nicotinic / Q000378:metabolism*
chemical_list: D000700:Analgesics; C526014:Chrna10 protein, mouse; C470699:Chrna10 protein, rat; C402445:Chrna9 protein, mouse; C498541:Chrna9 protein, rat; D020916:Conotoxins; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; C507383:alpha-conotoxin Vc1.1
keywords: pain; α-conotoxins; α9α10-nicotinic acetylcholine receptors