1. The nicotinic α6 subunit gene determines variability in chronic pain sensitivity via cross-inhibition of P2X2/3 receptors
- Author
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Weike Lai, Kelen Freitas, Shakir Al Sharari, Christopher I. Richards, M. Imad Damaj, Jaclyn Marcovitz, Michael R. Post, Jean-Sebastien Austin, Sarah C. R. Lummis, Luda Diatchenko, Sarah E Clarke, Ardem Patapoutian, Dennis A. Dougherty, Marshall Devor, Jeffrey S. Mogil, Dmitri V. Zaykin, Eske Kvanner Aasvang, Henry A. Lester, Loren J. Martin, John R. Walker, Walrati Limapichat, William Maixner, Jeff Janes, Reinhard Bittner, Feng Dai, Andrew I. Su, Shad B. Smith, Peter Maxwell Slepian, Jeffrey S. Wieskopf, Jayanti Mathur, Mona Alqazzaz, Samantha K. Segall, Jie Zhang, Uwe Maskos, Ryan M. Drenan, Alexander H. Tuttle, Henrik Kehlet, Inna Belfer, Jean-Pierre Changeux, Robert E. Sorge, Gary D. Slade, McGill University = Université McGill [Montréal, Canada], Novartis Research Foundation, California Institute of Technology (CALTECH), University of Cambridge [UK] (CAM), National Institutes of Health [Bethesda] (NIH), University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC), Virginia Commonwealth University (VCU), University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE), Purdue University [West Lafayette], King Saud University [Riyadh] (KSU), University of Copenhagen = Københavns Universitet (KU), Marienhospital Witten [Stuttgart], University of Kentucky, Neurobiologie intégrative des Systèmes cholinergiques (NISC), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Collège de France (CdF (institution)), The Hebrew University of Jerusalem (HUJ), The Scripps Research Institute [La Jolla], University of California [San Diego] (UC San Diego), University of California-University of California, Supported by the Canadian Institutes for Health Research and the Louise and Alan Edwards Foundation (J.S.M.), and the U.S. National Institutes of Health (D.A.D., H.A.L., A.P.)., We thank Taryn Earley, Takashi Miyamoto, and Matt Petrus for assistance with DRG dissection. We thank Sanjeev Ranade and Valerie Uzzell for data analysis., University of Copenhagen = Københavns Universitet (UCPH), University of Kentucky (UK), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), and The Scripps Research Institute [La Jolla, San Diego]
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Pathology ,MESH: Fluorescence Resonance Energy Transfer ,MESH: Mice, Mutant Strains ,[SDV]Life Sciences [q-bio] ,Receptors, Nicotinic ,Pharmacology ,MESH: Down-Regulation ,Nicotine ,Mice ,[SCCO]Cognitive science ,0302 clinical medicine ,Dorsal root ganglion ,Ganglia, Spinal ,Fluorescence Resonance Energy Transfer ,MESH: Animals ,MESH: Purinergic P2X Receptor Antagonists ,0303 health sciences ,biology ,CHRNA6 ,Chronic pain ,General Medicine ,3. Good health ,Nicotinic acetylcholine receptor ,medicine.anatomical_structure ,Allodynia ,Nicotinic agonist ,MESH: Receptors, Nicotinic ,Nociceptor ,MESH: Receptors, Purinergic P2X2 ,MESH: Ganglia, Spinal ,Chronic Pain ,medicine.symptom ,MESH: Receptors, Purinergic P2X3 ,medicine.drug ,medicine.medical_specialty ,Purinergic P2X Receptor Antagonists ,Down-Regulation ,Article ,03 medical and health sciences ,medicine ,Animals ,Humans ,MESH: Mice ,030304 developmental biology ,MESH: Humans ,business.industry ,[SCCO.NEUR]Cognitive science/Neuroscience ,medicine.disease ,Mice, Mutant Strains ,biology.protein ,MESH: Chronic Pain ,business ,Receptors, Purinergic P2X3 ,030217 neurology & neurosurgery ,Receptors, Purinergic P2X2 - Abstract
International audience; 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.
- Published
- 2015
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