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TitleMorphine hyperalgesia gated through microglia-mediated disruption of neuronal Cl⁻ homeostasis.
Publication TypeJournal Article
Year of Publication2013
AuthorsFerrini, Francesco, Tuan Trang, Theresa-Alexandra M. Mattioli, Sophie Laffray, Thomas Del'Guidice, Louis-Etienne Lorenzo, Annie Castonguay, Nicolas Doyon, Wenbo Zhang, Antoine G. Godin, Daniela Mohr, Simon Beggs, Karen Vandal, Jean-Martin Beaulieu, Catherine M. Cahill, Michael W. Salter, and Yves De Koninck
JournalNat Neurosci
Date Published2013 Feb
KeywordsAnimals, Biophysical Phenomena, Brain-Derived Neurotrophic Factor, CD11b Antigen, Chlorides, Down-Regulation, Gene Expression Regulation, Homeostasis, Hot Temperature, Hyperalgesia, Ion Channel Gating, Male, Membrane Potentials, Mice, Mice, Inbred C57BL, Mice, Transgenic, Microglia, Morphine, Motor Activity, Naloxone, Narcotic Antagonists, Narcotics, Neurons, Pain Threshold, Patch-Clamp Techniques, Protein Synthesis Inhibitors, Rats, Rats, Sprague-Dawley, Receptors, Purinergic P2X4, Ribosome Inactivating Proteins, Type 1, Rotarod Performance Test, Signal Transduction, Spinal Cord, Symporters, Time Factors, Touch, Vocalization, Animal

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.

Alternate JournalNat. Neurosci.
PubMed ID23292683
PubMed Central IDPMC4974077
Grant List134759-1 / / Canadian Institutes of Health Research / Canada
/ / Canadian Institutes of Health Research / Canada
/ / Howard Hughes Medical Institute / United States