Morphine hyperalgesia gated through microglia-mediated disruption of neuronal Cl− homeostasis
Nature neuroscience, 2013•nature.com
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 …
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 …
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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