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PRECLINICAL STUDY: Mechanisms of respiratory insufficiency induced by methadone overdose in rats
Author(s) -
Chevillard Lucie,
Mégarbane Bruno,
Baud Frédéric J.,
Risède Patricia,
Declèves Xavier,
Mager Donald,
Milan Nathalie,
Ricordel Ivan
Publication year - 2010
Publication title -
addiction biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.445
H-Index - 78
eISSN - 1369-1600
pISSN - 1355-6215
DOI - 10.1111/j.1369-1600.2009.00184.x
Subject(s) - naltrindole , methadone , medicine , respiratory system , anesthesia , antagonist , opioid , ventilation (architecture) , endocrinology , receptor antagonist , receptor , mechanical engineering , engineering
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 (mu1‐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 µg/ml) at lower concentrations than those necessary for PaCO 2 increase (EC 50 : 3.35 µg/ml). Similarly, increased T I (EC 50 : 0.501 µg/ml) was obtained at lower concentrations than those for T E (EC 50 : 4.83 µg/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.