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)

1 McGill University = Université McGill [Montréal, Canada]
2 Novartis Research Foundation
3 CALTECH - California Institute of Technology
4 CAM - University of Cambridge [UK]
5 NIH - National Institutes of Health [Bethesda]
6 UNC - University of North Carolina [Chapel Hill]
7 VCU - Virginia Commonwealth University
8 PITT - University of Pittsburgh
9 Purdue University [West Lafayette]
10 KSU - King Saud University [Riyadh]
11 UCPH - University of Copenhagen = Københavns Universitet
12 Marienhospital Witten [Stuttgart]
13 UK - University of Kentucky
14 NISC - Neurobiologie intégrative des Systèmes cholinergiques
15 CdF (institution) - Collège de France
16 HUJ - The Hebrew University of Jerusalem
17 The Scripps Research Institute [La Jolla, San Diego]

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.

Domains: Cognitive science; Life Sciences [q-bio]; Neuroscience

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, 2015, 7 (287), pp.287ra72 - 287ra72. ⟨10.1126/scitranslmed.3009986⟩. ⟨pasteur-01573816⟩