Morphine hyperalgesia gated through microglia-mediated disruption of neuronal Cl⁻ homeostasis.
Francesco Ferrini,Francesco Ferrini,Tuan Trang,Theresa-Alexandra M Mattioli,Sophie Laffray,Thomas Del’Guidice,Louis-Etienne Lorenzo,Annie Castonguay,Nicolas Doyon,Wen-Bo Zhang,Antoine G. Godin,Daniela Mohr,Simon Beggs,Karen Vandal,Jean-Martin Beaulieu,Catherine M. Cahill,Catherine M. Cahill,Michael W. Salter,Yves De Koninck +18 more
TLDR
The 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.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.read more
Citations
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Microglia emerge as central players in brain disease.
Michael W. Salter,Beth Stevens +1 more
TL;DR: Recent developments in the rapidly expanding understanding of the function, as well as the dysfunction, of microglia in disorders of the CNS are focused on.
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Glia and pain: Is chronic pain a gliopathy?
Ru-Rong Ji,Temugin Berta +1 more
TL;DR: Chronic pain could be a result of "gliopathy," that is, dysregulation of glial functions in the central and peripheral nervous system, and an update on recent advances is provided and remaining questions are discussed.
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Pain regulation by non-neuronal cells and inflammation.
TL;DR: This work reviews how non-neuronal cells interact with nociceptive neurons by secreting neuroactive signaling molecules that modulate pain and discusses new therapeutic strategies to control neuroinflammation for the prevention and treatment of chronic pain.
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Emerging targets in neuroinflammation-driven chronic pain
TL;DR: This Review focuses on emerging targets — such as chemokines, proteases and the WNT pathway — that promote spinal cord neuro inflammation and chronic pain and highlights the anti-inflammatory and pro-resolution lipid mediators that act on immune cells, glial cells and neurons to resolve neuroinflammation, synaptic plasticity and pain.
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Pathological pain and the neuroimmune interface
TL;DR: The current understanding of the contribution of central immune mechanisms to pathological pain is discussed, and how the heterogeneous immune functions of different cells in the CNS could be harnessed to develop new therapeutics for pain control is discussed.
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Jeffrey A. M. Coull,Simon Beggs,Dominic Boudreau,Dominick Boivin,Makoto Tsuda,Kazuhide Inoue,Claude Gravel,Michael W. Salter,Yves De Koninck +8 more
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Hans W. D. Matthes,Rafael Maldonado,Frédéric Simonin,Olga Valverde,Susan Slowe,Ian Kitchen,Katia Befort,Andrée Dierich,Marianne Le Meur,Pascal Dollé,Eleni T. Tzavara,Jacques Hanoune,Bernard P. Roques,Brigitte L. Kieffer +13 more
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