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Morphine hyperalgesia gated through microglia-mediated disruption of neuronal Cl− homeostasis
- Ferrini, Francesco;
- Trang, Tuan;
- Mattioli, Theresa-Alexandra M;
- Laffray, Sophie;
- Del'Guidice, Thomas;
- Lorenzo, Louis-Etienne;
- Castonguay, Annie;
- Doyon, Nicolas;
- Zhang, Wenbo;
- Godin, Antoine G;
- Mohr, Daniela;
- Beggs, Simon;
- Vandal, Karen;
- Beaulieu, Jean-Martin;
- Cahill, Catherine M;
- Salter, Michael W;
- De Koninck, Yves
- et al.
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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