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The nicotinic 6 subunit gene determines variability in chronic pain sensitivity via cross-inhibition of P2X2/3 receptors

Jeffrey. S. Wieskopf 1 Jayanti Mathur 2 Walrati Limapichat 3 Michael.R Post 3 Mona Al-Qazzaz 4 Robert Sorge 1 Loren.J Martin 1 Dmitri V. Zaykin 5 Shad B. Smith 6 Kelen Freitas 7 Jean Sebastien Austin 1 Feng Dai 8 Jie Zhang 2 Jaclyn Marcovitz 1 Alexander H. Tuttle 1 Peter M. Slepian 1 Sarah Clarke 1 Ryan M. Drenan 9 Jeff Janes 2 Shakir Al Sharari 10 Samantha K. Segall 6 Eske K. Aasvang 11 Weikke Lai 8 Reihnard Bittner 12 Christopher I. Richards 13 Gary D. Slade 6 Henrik Kehlet 11 John Walker 2 Uwe Maskos 14 Jean-Pierre Changeux 14, 15 Marshall Devor 16 William Maixner 6 Luda Diatchenko 1, 6 Inna Belfer 8 Dennis A. Dougherty 3 Andrew I. Su 17 Sarah C. R. Lummis 4 M. Imad Damaj 7 Henry A. Lester 3 Ardem Patapoutian 17 Jeffrey S. Mogil 1, *
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.
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https://hal-pasteur.archives-ouvertes.fr/pasteur-01573816
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Submitted on : Thursday, August 10, 2017 - 3:53:09 PM
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Jeffrey. S. Wieskopf, Jayanti Mathur, Walrati Limapichat, Michael.R Post, Mona Al-Qazzaz, et al.. The nicotinic 6 subunit gene determines variability in chronic pain sensitivity via cross-inhibition of P2X2/3 receptors. Science Translational Medicine, American Association for the Advancement of Science, 2015, 7 (287), pp.287ra72 - 287ra72. ⟨10.1126/scitranslmed.3009986⟩. ⟨pasteur-01573816⟩

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