Mechanisms of respiratory insufficiency induced by methadone overdose in rats

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 PaO₂ (P < 0.05) Respiratory effects as a function of plasma R-methadone concentrations showed a decrease in PaO ₂ (EC₅₀: 1.14 μg/ml) at lower concentrations than those necessary for PaCO₂ increase (EC₅₀: 3.35 μg/ml). Similarly, increased T_I (EC₅₀: 0.501 μg/ml) was obtained at lower concentrations than those for T_E (EC₅₀: 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.