title: Alpha9 nicotinic acetylcholine receptors and the treatment of pain.
abstract: Chronic pain is a vexing worldwide problem that causes substantial disability and consumes significant medical resources. Although there are numerous analgesic medications, these work through a small set of molecular mechanisms. Even when these medications are used in combination, substantial amounts of pain often remain. It is therefore highly desirable to develop treatments that work through distinct mechanisms of action. While agonists of nicotinic acetylcholine receptors (nAChRs) have been intensively studied, new data suggest a role for selective antagonists of nAChRs. alpha-Conotoxins are small peptides used offensively by carnivorous marine snails known as Conus. A subset of these peptides known as alpha-conotoxins RgIA and Vc1.1 produces both acute and long lasting analgesia. In addition, these peptides appear to accelerate the recovery of function after nerve injury, possibly through immune mediated mechanisms. Pharmacological analysis indicates that RgIA and Vc1.1 are selective antagonists of alpha9alpha10 nAChRs. A recent study also reported that these alpha9alpha10 antagonists are also potent GABA-B agonists. In the current study, we were unable to detect RgIA or Vc1.1 binding to or action on cloned GABA-B receptors expressed in HEK cells or Xenopus oocytes. We review the background, findings and implications of use of compounds that act on alpha9* nAChRs.(1).
authors.affiliation: Department of Psychiatry, University of Utah, Salt Lake City, UT 84132, USA. mcintosh.mike@gmail.com
authors.forename: J Michael
authors.initials: JM
authors.lastname: McIntosh
authors.forename: Nathan
authors.initials: N
authors.lastname: Absalom
authors.forename: Mary
authors.initials: M
authors.lastname: Chebib
authors.forename: Ana Belén
authors.initials: AB
authors.lastname: Elgoyhen
authors.forename: Michelle
authors.initials: M
authors.lastname: Vincler
mesh_terms: D000700:Analgesics / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D020916:Conotoxins / Q000494:pharmacology* / Q000627:therapeutic use; D058786:GABA-B Receptor Agonists; D006801:Humans; D018722:Nicotinic Agonists / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D010146:Pain / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism*; D055503:Protein Multimerization; D021122:Protein Subunits / Q000502:physiology; D018080:Receptors, GABA-B / Q000235:genetics / Q000502:physiology; D011978:Receptors, Nicotinic / Q000502:physiology*; D011994:Recombinant Proteins / Q000819:agonists / Q000235:genetics
chemical_list: D000700:Analgesics; C498540:CHRNA9 protein, human; C402445:Chrna9 protein, mouse; C498541:Chrna9 protein, rat; D020916:Conotoxins; D058786:GABA-B Receptor Agonists; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D021122:Protein Subunits; D018080:Receptors, GABA-B; D011978:Receptors, Nicotinic; D011994:Recombinant Proteins