Abstract

Chronic pain is highly variable between individuals, as is the response to analgesics. Although much of the variability in chronic pain and analgesic response is heritable, an understanding of the genetic determinants underlying this variability is rudimentary1. Here we show that variation within the coding sequence of the gene encoding the P2X7 receptor (P2X7R) affects chronic pain sensitivity in both mice and humans. P2X7Rs, which are members of the family of ionotropic ATP-gated receptors, have two distinct modes of function: they can function through their intrinsic cationic channel or by forming nonselective pores that are permeable to molecules with a mass of up to 900 Da2,3. Using genome-wide linkage analyses, we discovered an association between nerve-injury–induced pain behavior (mechanical allodynia) and the P451L mutation of the mouse P2rx7 gene, such that mice in which P2X7Rs have impaired pore formation as a result of this mutation showed less allodynia than mice with the pore-forming P2rx7 allele. Administration of a peptide corresponding to the P2X7R C-terminal domain, which blocked pore formation but not cation channel activity, selectively reduced nerve injury and inflammatory allodynia only in mice with the pore-forming P2rx7 allele. Moreover, in two independent human chronic pain cohorts, a cohort with pain after mastectomy and a cohort with osteoarthritis, we observed a genetic association between lower pain intensity and the hypofunctional His270 (rs7958311) allele of P2RX7. Our findings suggest that selectively targeting P2X7R pore formation may be a new strategy for individualizing the treatment of chronic pain.

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Acknowledgements

This research was supported by the US National Institutes of Health (NIH) (C.J.W., W.M., L.D., Z.S. and J.S.M.), the Louise and Alan Edwards Foundation (J.S.M.), the Canada Research Chairs program (M.W.S., J.S.M. and Z.S.), the Howard Hughes Medical Institute (M.W.S.), the Canadian Institutes of Health Research (M.W.S. and J.S.M.), the Krembil Foundation (M.W.S. and J.S.M.), the Ontario Research Foundation (M.W.S.) and Algynomics/Pfizer research funds (W.M., L.D.). R.E.S. was supported by an AstraZeneca–Alan Edwards Centre for Research on Pain postdoctoral fellowship. T.T. was supported by a Canadian Institutes of Health Research Fellowship. S.B.S. was supported by a National Research Service Award Fellowship from the NIH. D.V.Z. was supported by the Intramural Research Program of the NIH (National Institute of Environmental Health Sciences).

Author information

Author notes

    • Robert E Sorge
    •  & Tuan Trang

    These authors contributed equally to this work.

Affiliations

  1. Department of Psychology and Alan Edwards Centre for Research on Pain, McGill University, Montreal, Quebec, Canada.

    • Robert E Sorge
    • , Jennifer Ritchie
    • , Jean-Sebastien Austin
    •  & Jeffrey S Mogil
  2. Program in Neurosciences & Mental Health Hospital for Sick Children, Toronto, Ontario, Canada.

    • Tuan Trang
    • , Ruslan Dorfman
    • , Simon Beggs
    • , Heather Vander Meulen
    •  & Michael W Salter
  3. Center for Neurosensory Disorders, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

    • Shad B Smith
    • , William Maixner
    •  & Luda Diatchenko
  4. Algynomics Inc., Chapel Hill, North Carolina, USA.

    • Shad B Smith
    • , Gary D Slade
    • , William Maixner
    • , Luda Diatchenko
    •  & Jeffrey S Mogil
  5. National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA.

    • Dmitri V Zaykin
  6. Department of Neurobiology, Harvard Medical School, Boston, Massachusetts, USA.

    • Michael Costigan
    • , Teri A Herbert
    •  & Clifford J Woolf
  7. Faculties of Dentistry and of Medicine, University of Toronto, Toronto, Ontario, Canada.

    • Merav Yarkoni-Abitbul
    • , David Tichauer
    • , Ze'ev Seltzer
    •  & Michael W Salter
  8. Oncology Institute, Sheba Medical Centre, Ramat Gan, Israel.

    • Jessica Livneh
  9. Ein Hod, Hof Hacarmel, Israel.

    • Edith Gershon
  10. Department of Anesthesia, Stanford University School of Medicine, Stanford, California, USA.

    • Ming Zheng
    •  & Gary Peltz
  11. Pfizer Global Research and Development, Sandwich, UK.

    • Keith Tan
    •  & Sally L John
  12. Department of Dental Ecology, School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

    • Gary D Slade
  13. Thurston Arthritis Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina USA.

    • Joanne Jordan

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Contributions

R.E.S., T.T., R.D., S.B.S., S.B., J.R., J.-S.A., D.V.Z., H.V.M., M.C., T.A.H., M.Y.-A., D.T., E.G., M.Z., J.L. and G.P. generated data, performed analyses or both. R.E.S., S.B., C.J.W., W.M., L.D., Z.S., K.T., G.D.S., J.J., S.L.J., T.T., M.W.S. and J.S.M. contributed to the design of the study and supervised the analyses. R.E.S., T.T., M.W.S. and J.S.M. wrote the manuscript. All authors read and approved the final manuscript.

Competing interests

W.M., L.D. and S.B.S. are equity shareholders in Algynomics. W.M., L.D. and J.S.M. are officers in Algynomics.

Corresponding authors

Correspondence to Michael W Salter or Jeffrey S Mogil.

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DOI

https://doi.org/10.1038/nm.2710

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