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

Jeffrey S. Wieskopf, Jayanti Mathur, Walrati Limapichat, Michael R. Post, Mona Al-Qazzaz, Robert E. Sorge, Loren J. Martin, Dmitri V. Zaykin, Shad B. Smith, Kelen Freitas, Jean Sebastien Austin, Feng Dai, Jie Zhang, Jaclyn Marcovitz, Alexander H. Tuttle, Peter M. Slepian, Sarah Clarke, Ryan M. Drenan, Jeff Janes, Shakir Al SharariSamantha K. Segall, Eske K. Aasvang, Weike Lai, Reinhard Bittner, Christopher I. Richards, Gary D. Slade, Henrik Kehlet, John Walker, Uwe Maskos, Jean Pierre Changeux, Marshall Devor, William Maixner, Luda Diatchenko, Inna Belfer, Dennis A. Dougherty, Andrew I. Su, Sarah C R Lummis, M. Imad Damaj, Henry A. Lester, Ardem Patapoutian, Jeffrey S. Mogil*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

39 Scopus citations

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 a6 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 a6∗ 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.

Original languageEnglish (US)
JournalScience translational medicine
Volume7
Issue number287
DOIs
StatePublished - May 13 2015

ASJC Scopus subject areas

  • Medicine(all)

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