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首页> 外文期刊>Addiction biology >Mechanisms of respiratory insufficiency induced by methadone overdose in rats.
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Mechanisms of respiratory insufficiency induced by methadone overdose in rats.

机译：美沙酮过量引起的大鼠呼吸机能不全的机制。

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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.
机译：美沙酮可能引起呼吸抑制。我们旨在了解美沙酮对通气的影响以及每种阿片受体的作用。我们使用动脉血气和体积描记法研究了1.5、5和15 mg / kg（相当于致死剂量的80％-50％）对大鼠腹膜内美沙酮的呼吸作用。 OR拮抗剂，包括5分钟静脉内10 mg / kg纳洛酮嗪（mu-OR拮抗剂），24小时皮下30 mg / kg纳洛酮嗪（micro1-OR拮抗剂），45分钟3 mg / kg纳曲酮（δ-预先给予6小时的OR拮抗剂）和5 mg / kg的Nor-binaltorphimine（κ-OR拮抗剂）。使用高效液相色谱-质谱联用测定美沙酮对映异构体的血浆浓度。美沙酮剂量依赖的吸气时间（T（I））增加呈线性关系。仅在15 mg / kg时观察到呼吸抑制，其特征是呼气时间增加（T（E）），导致低氧血症和呼吸性酸中毒。静脉注射纳洛酮嗪完全逆转了所有美沙酮对通气的影响，而皮下纳洛酮嗪降低了其对pH值的影响（P <0.05），PaCO（2）（P <0.01）和T（E）（P <0.001），但对T的影响仅部分（I）（P <0.001）。纳曲酮减少了美沙酮对T（E）的影响（P <0.001）。 Nor-binaltorphimine增加对pH和PaO（2）的美沙酮相关作用（P <0.05）呼吸作用随血浆R-美沙酮浓度的变化而显示PaO（2）降低（EC（50）：1.14 microg / ml）浓度低于PaCO（2）增加所必需的浓度（EC（50）：3.35微克/毫升）。同样，以比T（E）（EC（50）：4.83 microg / ml）更低的浓度获得增加的T（I）（EC（50）：0.501 microg / ml）。美沙酮诱导的低氧血症是由mu-OR引起的，并由kappa-OR调节。此外，美沙酮诱导的T（E）升高是由mu1-和δ阿片受体引起的，而T（I）的升高则是由mu-OR引起的。

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