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Sci Transl Med. 2015 May 13;7(287):287ra72. doi: 10.1126/scitranslmed.3009986.

The nicotinic α6 subunit gene determines variability in chronic pain sensitivity via cross-inhibition of P2X2/3 receptors.

Author information

1
Department of Psychology and Alan Edwards Centre for Research on Pain, McGill University, Montreal, Quebec H3A 1B1, Canada.
2
Genomic Institute of the Novartis Research Foundation, San Diego, CA 92121, USA.
3
Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
4
Department of Biochemistry, University of Cambridge, Cambridge CB2 1QW, UK.
5
National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
6
Center for Neurosensory Disorders, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
7
Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23219, USA.
8
Departments of Anesthesiology and Human Genetics, University of Pittsburgh, Pittsburgh, PA 15213, USA.
9
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, USA.
10
Department of Pharmacology, King Saud University, P. O. Box 2457, Riyadh 11451, Saudi Arabia.
11
Section for Surgical Pathophysiology, Rigshospitalet, Copenhagen University, 2100 Copenhagen, Denmark.
12
Department of Surgery, Marienhospital Stuttgart, 70199 Stuttgart, Germany.
13
Department of Chemistry, University of Kentucky, Lexington, KY 40506, USA.
14
Department of Dental Ecology, School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
15
Neurobiologie Intégrative des Systèmes Cholinergiques, CNRS UMR 3571, Département de Neuroscience, Institute Pasteur, 75724 Paris, France.
16
Department of Cell and Developmental Biology, Institute of Life Sciences and Center for Research on Pain, Hebrew University of Jerusalem, Jerusalem 91904, Israel.
17
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.
18
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.
19
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
20
Department of Molecular and Cellular Neuroscience, The Scripps Research Institute, and Howard Hughes Medical Institute, La Jolla, CA 92037, USA.
21
Department of Psychology and Alan Edwards Centre for Research on Pain, McGill University, Montreal, Quebec H3A 1B1, Canada. jeffrey.mogil@mcgill.ca.

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.

PMID:
25972004
PMCID:
PMC5018401
DOI:
10.1126/scitranslmed.3009986
[Indexed for MEDLINE]
Free PMC Article

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