title: 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.affiliation: Institut Universitaire en Santé Mentale de Québec, Québec, Canada.
authors.forename: Francesco
authors.initials: F
authors.lastname: Ferrini
authors.forename: Tuan
authors.initials: T
authors.lastname: Trang
authors.forename: Theresa-Alexandra M
authors.initials: TA
authors.lastname: Mattioli
authors.forename: Sophie
authors.initials: S
authors.lastname: Laffray
authors.forename: Thomas
authors.initials: T
authors.lastname: Del'Guidice
authors.forename: Louis-Etienne
authors.initials: LE
authors.lastname: Lorenzo
authors.forename: Annie
authors.initials: A
authors.lastname: Castonguay
authors.forename: Nicolas
authors.initials: N
authors.lastname: Doyon
authors.forename: Wenbo
authors.initials: W
authors.lastname: Zhang
authors.forename: Antoine G
authors.initials: AG
authors.lastname: Godin
authors.forename: Daniela
authors.initials: D
authors.lastname: Mohr
authors.forename: Simon
authors.initials: S
authors.lastname: Beggs
authors.forename: Karen
authors.initials: K
authors.lastname: Vandal
authors.forename: Jean-Martin
authors.initials: JM
authors.lastname: Beaulieu
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Cahill
authors.forename: Michael W
authors.initials: MW
authors.lastname: Salter
authors.forename: Yves
authors.initials: Y
authors.lastname: De Koninck
mesh_terms: D000818:Animals; D055592:Biophysical Phenomena / Q000187:drug effects / Q000235:genetics; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D039481:CD11b Antigen / Q000235:genetics / Q000378:metabolism; D002712:Chlorides / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006706:Homeostasis / Q000187:drug effects*; D006358:Hot Temperature / Q000009:adverse effects; D006930:Hyperalgesia / Q000188:drug therapy*; D015640:Ion Channel Gating / Q000187:drug effects; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects* / Q000502:physiology; D009020:Morphine / Q000008:administration & dosage*; D009043:Motor Activity / Q000187:drug effects; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009294:Narcotics / Q000008:administration & dosage*; D009474:Neurons / Q000187:drug effects*; D017288:Pain Threshold / Q000187:drug effects; D018408:Patch-Clamp Techniques; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D058848:Receptors, Purinergic P2X4 / Q000235:genetics / Q000378:metabolism; D054789:Ribosome Inactivating Proteins, Type 1 / Q000494:pharmacology; D045442:Rotarod Performance Test; D000076985:Saporins; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013116:Spinal Cord / Q000166:cytology; D027981:Symporters / Q000378:metabolism; D013997:Time Factors; D014110:Touch; D014828:Vocalization, Animal / Q000187:drug effects; D000096922:K Cl- Cotransporters
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D039481:CD11b Antigen; D002712:Chlorides; D009020:Morphine; D009270:Naloxone; D009292:Narcotic Antagonists; D009294:Narcotics; D011500:Protein Synthesis Inhibitors; D058848:Receptors, Purinergic P2X4; D054789:Ribosome Inactivating Proteins, Type 1; D000076985:Saporins; D027981:Symporters; D000096922:K Cl- Cotransporters; C548227:P2rx4 protein, mouse