title: Mechanisms of respiratory insufficiency induced by methadone overdose in rats.
abstract: Methadone may cause respiratory depression. We aimed to understand methadone-related effects on ventilation as well as each opioid-receptor (OR) role. We studied the respiratory effects of intraperitoneal methadone at 1.5, 5, and 15 mg/kg (corresponding to 80% of the lethal dose-50%) in rats using arterial blood gases and plethysmography. OR antagonists, including intravenous 10 mg/kg-naloxonazine at 5 minutes (mu-OR antagonist), subcutaneous 30 mg/kg-naloxonazine at 24 hours (micro1-OR antagonist), 3 mg/kg-naltrindole at 45 minutes (delta-OR antagonist) and 5 mg/kg-Nor-binaltorphimine at 6 hours (kappa-OR antagonist) were pre-administered. Plasma concentrations of methadone enantiomers were measured using high-performance liquid chromatography coupled to mass-spectrometry. Methadone dose-dependent inspiratory time (T(I)) increase tended to be linear. Respiratory depression was observed only at 15 mg/kg and characterized by an increase in expiratory time (T(E)) resulting in hypoxemia and respiratory acidosis. Intravenous naloxonazine completely reversed all methadone-related effects on ventilation, while subcutaneous naloxonazine reduced its effects on pH (P < 0.05), PaCO(2) (P < 0.01) and T(E) (P < 0.001) but only partially on T(I) (P < 0.001). Naltrindole reduced methadone-related effects on T(E) (P < 0.001). Nor-binaltorphimine increased methadone-related effects on pH and PaO(2) (P < 0.05) Respiratory effects as a function of plasma R-methadone concentrations showed a decrease in PaO(2) (EC(50): 1.14 microg/ml) at lower concentrations than those necessary for PaCO(2) increase (EC(50): 3.35 microg/ml). Similarly, increased T(I) (EC(50): 0.501 microg/ml) was obtained at lower concentrations than those for T(E) (EC(50): 4.83 microg/ml). Methadone-induced hypoxemia is caused by mu-ORs and modulated by kappa-ORs. Additionally, methadone-induced increase in T(E) is caused by mu1- and delta-opioid receptors while increase in T(I) is caused by mu-ORs.
authors.affiliation: Université Paris-Descartes, Faculté de Pharmacie, Neuropsychopharmacologie des addictions, CNRS, UMR 7157, Paris, France.
authors.forename: Lucie
authors.initials: L
authors.lastname: Chevillard
authors.forename: Bruno
authors.initials: B
authors.lastname: Mégarbane
authors.forename: Frédéric J
authors.initials: FJ
authors.lastname: Baud
authors.forename: Patricia
authors.initials: P
authors.lastname: Risède
authors.forename: Xavier
authors.initials: X
authors.lastname: Declèves
authors.forename: Donald
authors.initials: D
authors.lastname: Mager
authors.forename: Nathalie
authors.initials: N
authors.lastname: Milan
authors.forename: Ivan
authors.initials: I
authors.lastname: Ricordel
mesh_terms: D000142:Acidosis, Respiratory / Q000139:chemically induced / Q000503:physiopathology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D062787:Drug Overdose / Q000503:physiopathology*; D045853:Exhalation / Q000187:drug effects / Q000502:physiology; D000860:Hypoxia / Q000139:chemically induced / Q000503:physiopathology; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D008297:Male; D008691:Methadone / Q000493:pharmacokinetics / Q000633:toxicity*; D009292:Narcotic Antagonists / Q000494:pharmacology; D009294:Narcotics / Q000493:pharmacokinetics / Q000633:toxicity*; D010100:Oxygen / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley; D011957:Receptors, Opioid / Q000187:drug effects* / Q000502:physiology; D017465:Receptors, Opioid, delta / Q000187:drug effects / Q000502:physiology; D017473:Receptors, Opioid, kappa / Q000187:drug effects / Q000502:physiology; D017450:Receptors, Opioid, mu / Q000187:drug effects / Q000502:physiology; D012131:Respiratory Insufficiency / Q000503:physiopathology*
chemical_list: D009292:Narcotic Antagonists; D009294:Narcotics; D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D010100:Oxygen; D008691:Methadone