Abstract
A major unresolved issue in treating pain is the paradoxical hyperalgesia produced by the gold-standard analgesic morphine and other opiates. We found that hyperalgesia-inducing treatment with morphine resulted in downregulation of the K+-Cl− co-transporter KCC2, impairing Cl− homeostasis in rat spinal lamina l neurons. Restoring the anion equilibrium potential reversed the morphine-induced hyperalgesia without affecting tolerance. The hyperalgesia was also reversed by ablating spinal microglia. Morphine hyperalgesia, but not tolerance, required μ opioid receptor–dependent expression of P2X4 receptors (P2X4Rs) in microglia and μ-independent gating of the release of brain-derived neurotrophic factor (BDNF) by P2X4Rs. Blocking BDNF-TrkB signaling preserved Cl− homeostasis and reversed the hyperalgesia. Gene-targeted mice in which Bdnf was deleted from microglia did not develop hyperalgesia to morphine. However, neither morphine antinociception nor tolerance was affected in these mice. Our findings dissociate morphine-induced hyperalgesia from tolerance and suggest the microglia-to-neuron P2X4-BDNF-KCC2 pathway as a therapeutic target for preventing hyperalgesia without affecting morphine analgesia.
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Acknowledgements
We thank K. Bachand for technical assistance with behavior, F. Rassendren (INSERM) for P2rx4−/− mice, C.J. Evans (National Institute on Drug Abuse) for (+)naloxone and J. Vlahakis for (+)naloxone polarimetric analysis. This paper is dedicated to the memory of Karen Vandal, who passed away during the course of this study. This work was supported by Canadian Institutes for Health Research (CIHR) grants to Y.D.K., M.W.S., C.M.C. and J.-M.B., by the Krembil Foundation (Y.D.K. and M.W.S.), the Regione Piemonte/University of Turin Fellowship Program (F.F.), the CIHR Fellowship program (T.T. and L.-E.L.), the Howard Hughes Medical Institute (M.W.S.), the Anne and Max Tanenbaum Chair Program (M.W.S.), the Canada Research Chairs Program (C.M.C., J.-M.B. and M.W.S.), the Fonds de la recherche en santé du Québec Chercheur National Program (Y.D.K.) and the Ontario Research Fund Research Excellence Program (M.W.S.).
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F.F., T.T., C.M.C., M.W.S. and Y.D.K. conceived and designed the project. C.M.C., J.-M.B., Y.D.K. and M.W.S. supervised the experiments. F.F., T.T., T.-A.M.M., S.L., T.D., L.-E.L., A.C., W.Z., D.M., S.B. and K.V. performed the experiments. N.D. performed computer simulations and contributed to interpretation of results. S.B. generated CD11b-cre; BdnfloxP/loxP mice. F.F., T.T., T.-A.M.M., S.L., T.D., L.-E.L., A.C., N.D., W.Z. and A.G.G. analyzed the data. F.F., T.T., M.W.S. and Y.D.K. wrote the manuscript. All of the authors read and discussed the manuscript.
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Ferrini, F., Trang, T., Mattioli, TA. et al. Morphine hyperalgesia gated through microglia-mediated disruption of neuronal Cl− homeostasis. Nat Neurosci 16, 183–192 (2013). https://doi.org/10.1038/nn.3295
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DOI: https://doi.org/10.1038/nn.3295
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