title: The nicotinic α6 subunit gene determines variability in chronic pain sensitivity via cross-inhibition of P2X2/3 receptors.
abstract: Chronic pain is a highly prevalent and poorly managed human health problem. We used microarray-based expression genomics in 25 inbred mouse strains to identify dorsal root ganglion (DRG)-expressed genetic contributors to mechanical allodynia, a prominent symptom of chronic pain. We identified expression levels of Chrna6, which encodes the α6 subunit of the nicotinic acetylcholine receptor (nAChR), as highly associated with allodynia. We confirmed the importance of α6* (α6-containing) nAChRs by analyzing both gain- and loss-of-function mutants. We find that mechanical allodynia associated with neuropathic and inflammatory injuries is significantly altered in α6* mutants, and that α6* but not α4* nicotinic receptors are absolutely required for peripheral and/or spinal nicotine analgesia. Furthermore, we show that Chrna6's role in analgesia is at least partially due to direct interaction and cross-inhibition of α6* nAChRs with P2X2/3 receptors in DRG nociceptors. Finally, we establish the relevance of our results to humans by the observation of genetic association in patients suffering from chronic postsurgical and temporomandibular pain.
authors.affiliation: Department of Psychology and Alan Edwards Centre for Research on Pain, McGill University, Montreal, Quebec H3A 1B1, Canada.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Wieskopf
authors.affiliation: Genomic Institute of the Novartis Research Foundation, San Diego, CA 92121, USA.
authors.forename: Jayanti
authors.initials: J
authors.lastname: Mathur
authors.affiliation: Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
authors.forename: Walrati
authors.initials: W
authors.lastname: Limapichat
authors.affiliation: Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Post
authors.affiliation: Department of Biochemistry, University of Cambridge, Cambridge CB2 1QW, UK.
authors.forename: Mona
authors.initials: M
authors.lastname: Al-Qazzaz
authors.affiliation: Department of Psychology and Alan Edwards Centre for Research on Pain, McGill University, Montreal, Quebec H3A 1B1, Canada.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Sorge
authors.affiliation: Department of Psychology and Alan Edwards Centre for Research on Pain, McGill University, Montreal, Quebec H3A 1B1, Canada.
authors.forename: Loren J
authors.initials: LJ
authors.lastname: Martin
authors.affiliation: National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
authors.forename: Dmitri V
authors.initials: DV
authors.lastname: Zaykin
authors.affiliation: Center for Neurosensory Disorders, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Shad B
authors.initials: SB
authors.lastname: Smith
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23219, USA.
authors.forename: Kelen
authors.initials: K
authors.lastname: Freitas
authors.affiliation: Department of Psychology and Alan Edwards Centre for Research on Pain, McGill University, Montreal, Quebec H3A 1B1, Canada.
authors.forename: Jean-Sebastien
authors.initials: JS
authors.lastname: Austin
authors.affiliation: Departments of Anesthesiology and Human Genetics, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Dai
authors.affiliation: Genomic Institute of the Novartis Research Foundation, San Diego, CA 92121, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Psychology and Alan Edwards Centre for Research on Pain, McGill University, Montreal, Quebec H3A 1B1, Canada.
authors.forename: Jaclyn
authors.initials: J
authors.lastname: Marcovitz
authors.affiliation: Department of Psychology and Alan Edwards Centre for Research on Pain, McGill University, Montreal, Quebec H3A 1B1, Canada.
authors.forename: Alexander H
authors.initials: AH
authors.lastname: Tuttle
authors.affiliation: Department of Psychology and Alan Edwards Centre for Research on Pain, McGill University, Montreal, Quebec H3A 1B1, Canada.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Slepian
authors.affiliation: Department of Psychology and Alan Edwards Centre for Research on Pain, McGill University, Montreal, Quebec H3A 1B1, Canada.
authors.forename: Sarah
authors.initials: S
authors.lastname: Clarke
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, USA.
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Drenan
authors.affiliation: Genomic Institute of the Novartis Research Foundation, San Diego, CA 92121, USA.
authors.forename: Jeff
authors.initials: J
authors.lastname: Janes
authors.affiliation: Department of Pharmacology, King Saud University, P. O. Box 2457, Riyadh 11451, Saudi Arabia.
authors.forename: Shakir
authors.initials: S
authors.lastname: Al Sharari
authors.affiliation: Center for Neurosensory Disorders, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Samantha K
authors.initials: SK
authors.lastname: Segall
authors.affiliation: Section for Surgical Pathophysiology, Rigshospitalet, Copenhagen University, 2100 Copenhagen, Denmark.
authors.forename: Eske K
authors.initials: EK
authors.lastname: Aasvang
authors.affiliation: Departments of Anesthesiology and Human Genetics, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors.forename: Weike
authors.initials: W
authors.lastname: Lai
authors.affiliation: Department of Surgery, Marienhospital Stuttgart, 70199 Stuttgart, Germany.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Bittner
authors.affiliation: Department of Chemistry, University of Kentucky, Lexington, KY 40506, USA.
authors.forename: Christopher I
authors.initials: CI
authors.lastname: Richards
authors.affiliation: Department of Dental Ecology, School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Gary D
authors.initials: GD
authors.lastname: Slade
authors.affiliation: Section for Surgical Pathophysiology, Rigshospitalet, Copenhagen University, 2100 Copenhagen, Denmark.
authors.forename: Henrik
authors.initials: H
authors.lastname: Kehlet
authors.affiliation: Genomic Institute of the Novartis Research Foundation, San Diego, CA 92121, USA.
authors.forename: John
authors.initials: J
authors.lastname: Walker
authors.affiliation: Neurobiologie Intégrative des Systèmes Cholinergiques, CNRS UMR 3571, Département de Neuroscience, Institute Pasteur, 75724 Paris, France.
authors.forename: Uwe
authors.initials: U
authors.lastname: Maskos
authors.affiliation: Neurobiologie Intégrative des Systèmes Cholinergiques, CNRS UMR 3571, Département de Neuroscience, Institute Pasteur, 75724 Paris, France.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Changeux
authors.affiliation: Department of Cell and Developmental Biology, Institute of Life Sciences and Center for Research on Pain, Hebrew University of Jerusalem, Jerusalem 91904, Israel.
authors.forename: Marshall
authors.initials: M
authors.lastname: Devor
authors.affiliation: Center for Neurosensory Disorders, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: William
authors.initials: W
authors.lastname: Maixner
authors.affiliation: Center for Neurosensory Disorders, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Faculty of Dentistry, Department of Anesthesia, and Alan Edwards Centre for Research on Pain, McGill University, Montreal, Quebec H3A 1G1, Canada.
authors.forename: Luda
authors.initials: L
authors.lastname: Diatchenko
authors.affiliation: Departments of Anesthesiology and Human Genetics, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors.forename: Inna
authors.initials: I
authors.lastname: Belfer
authors.affiliation: Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
authors.forename: Dennis A
authors.initials: DA
authors.lastname: Dougherty
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Andrew I
authors.initials: AI
authors.lastname: Su
authors.affiliation: Department of Biochemistry, University of Cambridge, Cambridge CB2 1QW, UK.
authors.forename: Sarah C R
authors.initials: SC
authors.lastname: Lummis
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23219, USA.
authors.forename: M
authors.initials: M
authors.lastname: Imad Damaj
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
authors.forename: Henry A
authors.initials: HA
authors.lastname: Lester
authors.affiliation: Department of Molecular and Cellular Neuroscience, The Scripps Research Institute, and Howard Hughes Medical Institute, La Jolla, CA 92037, USA.
authors.forename: Ardem
authors.initials: A
authors.lastname: Patapoutian
authors.affiliation: Department of Psychology and Alan Edwards Centre for Research on Pain, McGill University, Montreal, Quebec H3A 1B1, Canada. jeffrey.mogil@mcgill.ca.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Mogil
mesh_terms: D000818:Animals; D059350:Chronic Pain / Q000235:genetics*; D015536:Down-Regulation; D031541:Fluorescence Resonance Energy Transfer; D005727:Ganglia, Spinal / Q000378:metabolism; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D058920:Purinergic P2X Receptor Antagonists / Q000494:pharmacology; D011978:Receptors, Nicotinic / Q000235:genetics*; D058476:Receptors, Purinergic P2X2 / Q000378:metabolism*; D058477:Receptors, Purinergic P2X3 / Q000378:metabolism*
chemical_list: D058920:Purinergic P2X Receptor Antagonists; D011978:Receptors, Nicotinic; D058476:Receptors, Purinergic P2X2; D058477:Receptors, Purinergic P2X3; C104518:nicotinic receptor alpha6