title: Constitutive mu opioid receptor activation as a regulatory mechanism underlying narcotic tolerance and dependence.
abstract: Chronic administration of narcotic mu opioid agonists results in tolerance and dependence. We propose that agonist stimulation causes a gradual conversion of mu receptors to a constitutively active state (mu*) as a key step in tolerance and physical dependence. We provide evidence in support of the existence of mu* in human neuroblastoma cells, SH-SY5Y, and mu* upregulation during morphine treatment. Naloxone blocked mu* activity, acting as an antagonist with negative intrinsic activity which accounts for its high potency in eliciting withdrawal. In contrast, the mu selective antagonist CTAP did not affect mu* activity but inhibited naloxone's effect. The protein kinase inhibitor H7 was found to suppress mu* formation, suggesting that mu* is phosphorylated. In a model of acute morphine tolerance/dependence in mice, H7 prevented naloxone induced withdrawal jumping and reversed morphine (antinociceptive) tolerance. CTAP caused only mild withdrawal and attenuated naloxone induced withdrawal, as predicted for an antagonist without negative activity. These results support a role for constitutive mu receptor activation in narcotic tolerance and dependence, affording potential separation of acute and chronic narcotic effects.
authors.affiliation: Department of Pharmacy, University of California, San Francisco 94143-0446.
authors.forename: Z
authors.initials: Z
authors.lastname: Wang
authors.forename: E J
authors.initials: EJ
authors.lastname: Bilsky
authors.forename: F
authors.initials: F
authors.lastname: Porreca
authors.forename: W
authors.initials: W
authors.lastname: Sadée
mesh_terms: D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D002552:Cerebral Ventricles / Q000187:drug effects / Q000502:physiology* / Q000503:physiopathology; D000242:Cyclic AMP / Q000378:metabolism; D004361:Drug Tolerance; D006706:Homeostasis; D006801:Humans; D007276:Injections, Intraventricular; D007278:Injections, Spinal; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009020:Morphine / Q000633:toxicity*; D009021:Morphine Dependence / Q000503:physiopathology*; D009270:Naloxone / Q000008:administration & dosage / Q000494:pharmacology*; D009447:Neuroblastoma; D017450:Receptors, Opioid, mu / Q000187:drug effects / Q000502:physiology*; D013116:Spinal Cord / Q000187:drug effects / Q000502:physiology* / Q000503:physiopathology; D013375:Substance Withdrawal Syndrome / Q000503:physiopathology*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
chemical_list: D017450:Receptors, Opioid, mu; D009270:Naloxone; D009020:Morphine; D000242:Cyclic AMP; D015056:1-Methyl-3-isobutylxanthine