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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Biophysical Phenomena / drug effects
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Biophysical Phenomena / genetics
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Brain-Derived Neurotrophic Factor / genetics
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Brain-Derived Neurotrophic Factor / metabolism
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CD11b Antigen / genetics
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CD11b Antigen / metabolism
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Chlorides / metabolism*
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Down-Regulation / drug effects
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Gene Expression Regulation / drug effects
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Homeostasis / drug effects*
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Hot Temperature / adverse effects
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Hyperalgesia / drug therapy*
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Ion Channel Gating / drug effects
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K Cl- Cotransporters
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Male
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Membrane Potentials / drug effects
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Microglia / drug effects*
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Microglia / physiology
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Morphine / administration & dosage*
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Motor Activity / drug effects
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Naloxone / pharmacology
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Narcotic Antagonists / pharmacology
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Narcotics / administration & dosage*
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Neurons / drug effects*
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Pain Threshold / drug effects
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Patch-Clamp Techniques
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Protein Synthesis Inhibitors / pharmacology
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Rats
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Rats, Sprague-Dawley
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Receptors, Purinergic P2X4 / genetics
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Receptors, Purinergic P2X4 / metabolism
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Ribosome Inactivating Proteins, Type 1 / pharmacology
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Rotarod Performance Test
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Saporins
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Signal Transduction / drug effects
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Signal Transduction / genetics
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Spinal Cord / cytology
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Symporters / metabolism
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Time Factors
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Touch
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Vocalization, Animal / drug effects
Substances
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Brain-Derived Neurotrophic Factor
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CD11b Antigen
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Chlorides
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Narcotic Antagonists
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Narcotics
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P2rx4 protein, mouse
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Protein Synthesis Inhibitors
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Receptors, Purinergic P2X4
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Ribosome Inactivating Proteins, Type 1
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Symporters
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Naloxone
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Morphine
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Saporins