Document Detail

Morphine hyperalgesia gated through microglia-mediated disruption of neuronal Cl⁻ homeostasis.
MedLine Citation:
PMID:  23292683     Owner:  NLM     Status:  MEDLINE    
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.
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
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2013-01-06
Journal Detail:
Title:  Nature neuroscience     Volume:  16     ISSN:  1546-1726     ISO Abbreviation:  Nat. Neurosci.     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-01-28     Completed Date:  2013-03-22     Revised Date:  2013-04-01    
Medline Journal Info:
Nlm Unique ID:  9809671     Medline TA:  Nat Neurosci     Country:  United States    
Other Details:
Languages:  eng     Pagination:  183-92     Citation Subset:  IM    
Institut Universitaire en Santé Mentale de Québec, Québec, Canada.
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MeSH Terms
Antigens, CD11b / genetics,  metabolism
Biophysical Processes / drug effects,  genetics
Brain-Derived Neurotrophic Factor / genetics,  metabolism
Chlorides / metabolism*
Down-Regulation / drug effects
Gene Expression Regulation / drug effects
Homeostasis / drug effects*
Hot Temperature / adverse effects
Hyperalgesia / drug therapy*
Ion Channel Gating / drug effects
Membrane Potentials / drug effects
Mice, Inbred C57BL
Mice, Transgenic
Microglia / drug effects*,  physiology
Morphine / administration & dosage*
Motor Activity / drug effects
Naloxone / pharmacology
Narcotic Antagonists / pharmacology
Narcotics / administration & dosage*
Neurons / drug effects*
Pain Threshold / drug effects
Patch-Clamp Techniques
Protein Synthesis Inhibitors / pharmacology
Rats, Sprague-Dawley
Receptors, Purinergic P2X4 / genetics,  metabolism
Ribosome Inactivating Proteins, Type 1 / pharmacology
Rotarod Performance Test
Signal Transduction / drug effects,  genetics
Spinal Cord / cytology
Symporters / metabolism
Time Factors
Vocalization, Animal / drug effects
Grant Support
//Canadian Institutes of Health Research; //Howard Hughes Medical Institute
Reg. No./Substance:
0/Antigens, CD11b; 0/Brain-Derived Neurotrophic Factor; 0/Chlorides; 0/Narcotic Antagonists; 0/Narcotics; 0/P2rx4 protein, mouse; 0/Protein Synthesis Inhibitors; 0/Receptors, Purinergic P2X4; 0/Ribosome Inactivating Proteins, Type 1; 0/Symporters; 0/potassium-chloride symporters; 465-65-6/Naloxone; 57-27-2/Morphine; EC
Comment In:
Nat Rev Neurosci. 2013 Mar;14(3):154   [PMID:  23340603 ]

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