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

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.

• Authors: 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
• Journal: Nature neuroscience (Nat Neurosci) Vol. 16 Issue 2 Pg. 183-92 (Feb 2013) ISSN: 1546-1726 [Electronic] United States
• PMID: 23292683 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 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
• Naloxone
• Morphine
• Saporins

Topics

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