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Morphine hyperalgesia gated through microglia-mediated disruption of neuronal Cl− homeostasis
Francesco Ferrini, 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 & Yves De Koninck
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.
