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


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.

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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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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.

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Correspondence to Michael W Salter or Jeffrey S Mogil.

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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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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).

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