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Genetically determined P2X7 receptor pore formation regulates variability in chronic pain sensitivity

Nature Medicine volume 18, pages 595–599 (2012)Cite this article

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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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Figure 1: Haplotype mapping of SNI-induced mechanical allodynia reveals a genetic association with the P451L variant of the mouse P2rx7 gene.
Figure 2: BzATP causes calcein dye loss from the representative Pro451-carrying A/J mouse strain but not the Leu451-carrying B10.D2 mouse strain.
Figure 3: Treatment with the TAT-P451 peptide prevents and reverses pore formation induced by BzATP and reverses the mechanical allodynia caused by peripheral nerve injury (SNI) or inflammation (CFA) in A/J mice.
Figure 4: Genetic association of the human P2RX7 gene with chronic pain.

References

  1. Lacroix-Fralish, M.L. & Mogil, J.S. Progress in genetic studies of pain and analgesia. Annu. Rev. Pharmacol. Toxicol. 49, 97–121 (2009).

    Article  CAS  Google Scholar 

  2. Surprenant, A., Rassendren, F., Kawashima, E., North, R.A. & Buell, G. The cytolytic P2Z receptor for extracellular ATP identified as a P2X receptor (P2X7). Science 272, 735–738 (1996).

    Article  CAS  Google Scholar 

  3. Locovei, S., Scemes, E., Qiu, F., Spray, D.C. & Dahl, G. Pannexin1 is part of the pore forming unit of the P2X7 receptor death complex. FEBS Lett. 581, 483–488 (2007).

    Article  CAS  Google Scholar 

  4. Liao, G. et al. In silico genetics: identification of a functional element regulating H2-Eα gene expression. Science 306, 690–695 (2004).

    Article  CAS  Google Scholar 

  5. Adriouch, S. et al. A natural P451L mutation in the cytoplasmic domain impairs the function of the mouse P2X7 receptor. J. Immunol. 169, 4108–4112 (2002).

    Article  CAS  Google Scholar 

  6. Iglesias, R. et al. P2X7 receptor-Pannexin 1 complex: pharmacology and signaling. Am. J. Physiol. Cell Physiol. 295, C752–C760 (2008).

    Article  CAS  Google Scholar 

  7. Lariviere, W.R. et al. Heritability of nociception. III. Genetic relationships among commonly used assays of nociception and hypersensitivity. Pain 97, 75–86 (2002).

    Article  Google Scholar 

  8. Fuller, S.J., Stokes, L., Skarratt, K.K., Gu, B.J. & Wiley, J.S. Genetics of the P2X7 receptor and human disease. Purinergic Signal. 5, 257–262 (2009).

    Article  CAS  Google Scholar 

  9. Bradley, H.J. et al. Residues 155 and 348 contribute to the determination of P2X7 receptor function via distinct mechanisms revealed by single-nucleotide polymorphisms. J. Biol. Chem. 286, 8176–8187 (2011).

    Article  CAS  Google Scholar 

  10. Stokes, L. et al. Two haplotypes of the P2X7 receptor containing the Ala-348 to Thr polymorphism exhibit a gain-of-function effect and enhanced interleukin-1β secretion. FASEB J. 24, 2916–2927 (2010).

    Article  CAS  Google Scholar 

  11. Zaykin, D.V. Optimally weighted Z-test is a powerful method for combining probabilities in meta-analysis. J. Evol. Biol. 24, 1836–1841 (2011).

    Article  CAS  Google Scholar 

  12. Chessell, I.P. et al. Disruption of the P2X7 purinoceptor gene abolishes chronic inflammatory and neuropathic pain. Pain 114, 386–396 (2005).

    Article  CAS  Google Scholar 

  13. Clark, A.K. et al. P2X7-dependent release of interleukin-1β and nociception in the spinal cord following lipopolysaccharide. J. Neurosci. 30, 573–582 (2010).

    Article  CAS  Google Scholar 

  14. Honore, P. et al. A-740003 [N-(1-\{[(Cyanoimino)(5-quinolinylamino) methyl]amino}-2,2-dimethylpropyl)-2-(3,4-dimethoxyphenyl)acetamide], a novel and selective P2X7 receptor antagonist, dose-dependently reduces neuropathic pain in the rat. J. Pharmacol. Exp. Ther. 319, 1376–1385 (2006).

    Article  CAS  Google Scholar 

  15. McGaraughty, S. et al. P2X7-related modulation of pathological nociception in rats. Neuroscience 146, 1817–1828 (2007).

    Article  CAS  Google Scholar 

  16. Broom, D.C. et al. Characterization of N-(Adamantan-1-ylmethyl)-5-[(3R-aminopyrrolidin-1-yl)methyl]-2-chloro-benzamide, a P2X7 antagonist in animal models of pain and inflammation. J. Pharmacol. Exp. Ther. 327, 620–633 (2008).

    Article  CAS  Google Scholar 

  17. Dell'Antonio, G., Quattrini, A., Dal Cin, E., Fulgenzi, A. & Ferrero, M.E. Antinociceptive effect of a new P2Z/P2X7 antagonist, oxidized ATP, in arthritic rats. Neurosci. Lett. 327, 87–90 (2002).

    Article  CAS  Google Scholar 

  18. Jarvis, M.F. The neuron-glial purinergic receptor ensemble in chronic pain states. Trends Neurosci. 33, 48–57 (2010).

    Article  CAS  Google Scholar 

  19. Pelegrin, P. & Surprenant, A. The P2X7 receptor–pannexin connection to dye uptake and IL-1β release. Purinergic Signal. 5, 129–137 (2009).

    Article  CAS  Google Scholar 

  20. Di Virgilio, F. Liaisons dangereuses: P2X7 and the inflammasome. Trends Pharmacol. Sci. 28, 465–472 (2007).

    Article  CAS  Google Scholar 

  21. Mogil, J.S. & Chanda, M.L. The case for the inclusion of female subjects in basic science studies of pain. Pain 117, 1–5 (2005).

    Article  Google Scholar 

  22. Mogil, J.S. et al. Hypolocomotion, asymmetrically directed behaviors (licking, lifting, flinching, and shaking) and dynamic weight bearing (gait) changes are not measures of neuropathic pain in mice. Mol. Pain 6, 34 (2010).

    Article  Google Scholar 

  23. Chaplan, S.R., Bach, F.W., Pogrel, J.W., Chung, J.M. & Yaksh, T.L. Quantitative assessment of tactile allodynia evoked by unilateral ligation of the fifth and sixth lumbar nerves in the rat. J. Neurosci. Methods 53, 55–63 (1994).

    Article  CAS  Google Scholar 

  24. Callahan, B.L., Gil, A.S.C., Levesque, A. & Mogil, J.S. Modulation of mechanical and thermal nociceptive sensitivity in the laboratory mouse by behavioral state. J. Pain 9, 174–184 (2008).

    Article  Google Scholar 

  25. Decosterd, I. & Woolf, C.J. Spared nerve injury: an animal model of persistent peripheral neuropathic pain. Pain 87, 149–158 (2000).

    Article  CAS  Google Scholar 

  26. Shields, S.D., Eckert, W.A. III & Basbaum, A.I. Spared nerve injury model of neuropathic pain in the mouse: a behavioral and anatomic analysis. J. Pain 4, 465–470 (2003).

    Article  Google Scholar 

  27. Grupe, A. et al. In silico mapping of complex disease-related traits in mice. Science 292, 1915–1918 (2001).

    Article  CAS  Google Scholar 

  28. Wang, J., Liao, G., Usuka, J. & Peltz, G. Computational genetics: from mouse to human. Trends Genet. 21, 526–532 (2005).

    Article  CAS  Google Scholar 

  29. Salter, M.W. & Hicks, J.L. ATP causes release of intracellular Ca2+ via the phospholipase Cβ/IP3 pathway in astrocytes from the dorsal spinal cord. J. Neurosci. 15, 2961–2971 (1995).

    Article  CAS  Google Scholar 

  30. Jiang, L.H., Mackenzie, A.B., North, R.A. & Surprenant, A. Brilliant Blue G selectievly blocks ATP-gated rat P2X7 receptors. Mol. Pharmacol. 58, 82–88 (2000).

    Article  CAS  Google Scholar 

Download references

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).

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Author notes

  1. Robert E Sorge and Tuan Trang: These authors contributed equally to this work.

Authors and 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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  1. Robert E Sorge
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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.

Corresponding authors

Correspondence to Michael W Salter or Jeffrey S Mogil.

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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.

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Supplementary Figures 1–6, Supplementary Tables 1–3 and Supplementary Methods (PDF 2464 kb)

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Sorge, R., Trang, T., Dorfman, R. et al. Genetically determined P2X7 receptor pore formation regulates variability in chronic pain sensitivity. Nat Med 18, 595–599 (2012). https://doi.org/10.1038/nm.2710

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