Morphine hyperalgesia gated through microglia-mediated disruption of neuronal Cl⁻ homeostasis

Nat Neurosci. 2013 Feb;16(2):183-92. doi: 10.1038/nn.3295. Epub 2013 Jan 6.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biophysical Phenomena / drug effects
  • Biophysical Phenomena / genetics
  • Brain-Derived Neurotrophic Factor / genetics
  • Brain-Derived Neurotrophic Factor / metabolism
  • CD11b Antigen / genetics
  • CD11b Antigen / 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
  • Male
  • Membrane Potentials / drug effects
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Microglia / drug effects*
  • Microglia / 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
  • Rats, Sprague-Dawley
  • Receptors, Purinergic P2X4 / genetics
  • Receptors, Purinergic P2X4 / metabolism
  • Ribosome Inactivating Proteins, Type 1 / pharmacology
  • Rotarod Performance Test
  • Saporins
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Spinal Cord / cytology
  • Symporters / metabolism
  • Time Factors
  • Touch
  • Vocalization, Animal / drug effects

Substances

  • Brain-Derived Neurotrophic Factor
  • CD11b Antigen
  • Chlorides
  • Narcotic Antagonists
  • Narcotics
  • P2rx4 protein, mouse
  • Protein Synthesis Inhibitors
  • Receptors, Purinergic P2X4
  • Ribosome Inactivating Proteins, Type 1
  • Symporters
  • potassium-chloride symporters
  • Naloxone
  • Morphine
  • Saporins