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

Wieskopf, Jeffrey S. and Limapichat, Walrati and Post, Michael R. and Dougherty, Dennis A. and Lester, Henry A. (2015) The nicotinic α6 subunit gene determines variability in chronic pain sensitivity via cross-inhibition of P2X2/3 receptors. Science Translational Medicine, 7 (287). Art. No. 287ra72. ISSN 1946-6234. PMCID PMC5018401. doi:10.1126/scitranslmed.3009986. https://resolver.caltech.edu/CaltechAUTHORS:20150519-092649728

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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.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1126/scitranslmed.3009986DOIArticle
http://stm.sciencemag.org/content/7/287/287ra72PublisherArticle
http://stm.sciencemag.org/content/7/287/287ra72/suppl/DC1PublisherSupplementary Material
http://www.genenetwork.orgOrganizationGeneNetwork Database
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5018401PubMed CentralArticle
ORCID:
AuthorORCID
Post, Michael R.0000-0002-3214-7619
Dougherty, Dennis A.0000-0003-1464-2461
Lester, Henry A.0000-0002-5470-5255
Additional Information:© 2015 American Association for the Advancement of Science. Submitted 7 July 2014; accepted 11 March 2015; published 13 May 2015. We thank T. Earley, T. Miyamoto, and M. Petrus for assistance with DRG dissection. We thank S. Ranade and V. Uzzell for data analysis. Funding: Supported by the Canadian Institutes for Health Research and the Louise and Alan Edwards Foundation (J.S.M.) and the NIH (D.A.D., H.A.L., and A.P.). Author contributions: The study was conceived by A.P. and J.S.M. and designed by J.S.W., L.D., I.B., M.I.D., H.A.L., A.P., and J.S.M. J.S.W., J. Mathur, W.L., M.R.P., M.A.-Q., R.E.S., L.J.M., K.F., J.-S.A., J.Z., J. Marcovitz, A.H.T., P.M.S., S.C., J.J., S.A.S., E.K.A., R.B., C.I.R., H.K., and J.W. collected data. D.V.Z., S.B.S., F.D., R.M.D., S.K.S., W.L., G.D.S., and A.I.S. analyzed data. U.M., J.-P.C., and M.D. provided reagents or data. W.M., L.D., I.B., D.A.D., S.C.R.L., M.I.D., H.A.L., A.P., and J.S.M. supervised the collection of data, contributed to its interpretation, and edited the manuscript. J.S.W. and J.S.M. wrote the manuscript. Competing interests: The authors declare that they have no competing interests. Data and materials availability: The expression genomics data for this study have been deposited into the GeneNetwork Database (www.genenetwork.org).
Funders:
Funding AgencyGrant Number
Canadian Institutes for Health ResearchUNSPECIFIED
Louise and Alan Edwards FoundationUNSPECIFIED
NIHUNSPECIFIED
Issue or Number:287
PubMed Central ID:PMC5018401
DOI:10.1126/scitranslmed.3009986
Record Number:CaltechAUTHORS:20150519-092649728
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20150519-092649728
Official Citation:J. S. Wieskopf, J. Mathur, W. Limapichat, M. R. Post, M. Al-Qazzaz, R. E. Sorge, L. J. Martin, D. V. Zaykin, S. B. Smith, K. Freitas, J.-S. Austin, F. Dai, J. Zhang, J. Marcovitz, A. H. Tuttle, P. M. Slepian, S. Clarke, R. M. Drenan, J. Janes, S. Al Sharari, S. K. Segall, E. K. Aasvang, W. Lai, R. Bittner, C. I. Richards, G. D. Slade, H. Kehlet, J. Walker, U. Maskos, J.- P. Changeux, M. Devor, W. Maixner, L. Diatchenko, I. Belfer, D. A. Dougherty, A. I. Su, S. C. R. Lummis, M. Imad Damaj, H. A. Lester, A. Patapoutian, J. S. Mogil, The nicotinic α6 subunit gene determines variability in chronic pain sensitivity via cross-inhibition of P2X2/3 receptors. Sci. Transl. Med. 7, 287ra72 (2015).
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:57644
Collection:CaltechAUTHORS
Deposited By: Jason Perez
Deposited On:19 May 2015 18:23
Last Modified:10 Nov 2021 21:53

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