Roberts S M, Skoulis N P, James R C
Biochem Pharmacol. 1987 Sep 15;36(18):3001-5. doi: 10.1016/0006-2952(87)90215-2.
Morphine administration has been associated with a decrease in hepatic glutathione (GSH) and an increase in the hepatotoxicity of compounds dependent upon GSH for detoxification. In this study, intraperitoneal administration of 100 mg/kg morphine in mice resulted in approximately a 25% decrease in hepatic GSH. The same magnitude of GSH depletion was also observed following intracerebroventricular (i.c.v.) injection of 100 micrograms of morphine, but no effect was observed when 100 micrograms of morphine was administered intravenously. Pretreating animals with either yohimbine (5 mg/kg, i.p.) or prazosin (5 mg/kg, i.p.) resulted in a partial blockade of i.c.v. morphine-induced change in hepatic glutathione concentrations. Adrenalectomy prior to i.c.v. morphine treatment completely prevented morphine-induced changes in hepatic GSH concentrations; however, the morphine response was restored in adrenalectomized mice supplemented with hydrocortisone (2.5 mg/kg). No effect on the ability of i.c.v. morphine to diminish GSH concentrations in the liver was observed following pretreatment with either propranolol (20 mg/kg, i.p.), atropine (1 mg/kg, i.p.), hexamethonium (15 mg/kg, s.c.), or destruction of peripheral adrenergic nerve terminals with 6-hydroxydopamine (30 mg/kg, i.p.). It is concluded that hepatocellular GSH concentrations may be diminished as a consequence of a central action of morphine. The response by liver GSH to this action does not appear to be mediated through adrenal medullary release of catecholamines or by autonomic stimulation of the liver. While corticosteroids are a necessary component of this response, their role is probably permissive. The ability of both prazosin and yohimbine to antagonize the effect of i.c.v. morphine on hepatic GSH, coupled with the apparent absence of a peripheral catecholaminergic mechanism, suggests that the adrenergic interaction with the i.c.v. morphine effect is also of central origin. Thus, the results of this study show that the central effects of morphine can result in a decrease in hepatic GSH, and that this effect is not mediated by a peripheral catecholaminergic mechanism.
吗啡给药与肝脏谷胱甘肽（GSH）减少以及依赖GSH进行解毒的化合物肝毒性增加有关。在本研究中，给小鼠腹腔注射100mg/kg吗啡导致肝脏GSH下降约25%。脑室内（i.c.v.）注射100μg吗啡后也观察到相同程度的GSH消耗，但静脉注射100μg吗啡时未观察到效果。用育亨宾（5mg/kg，腹腔注射）或哌唑嗪（5mg/kg，腹腔注射）预处理动物导致i.c.v.吗啡诱导的肝脏谷胱甘肽浓度变化部分受阻。在i.c.v.吗啡治疗前进行肾上腺切除术可完全预防吗啡诱导的肝脏GSH浓度变化；然而，补充氢化可的松（2.5mg/kg）的肾上腺切除小鼠中吗啡反应得以恢复。用普萘洛尔（20mg/kg，腹腔注射）、阿托品（1mg/kg，腹腔注射）、六甲铵（15mg/kg，皮下注射）预处理或用6-羟基多巴胺（30mg/kg，腹腔注射）破坏外周肾上腺素能神经末梢后，未观察到i.c.v.吗啡降低肝脏GSH浓度能力的影响。结论是，肝细胞GSH浓度可能因吗啡的中枢作用而降低。肝脏GSH对该作用的反应似乎不是通过肾上腺髓质释放儿茶酚胺或通过自主神经对肝脏的刺激介导的。虽然皮质类固醇是该反应的必要组成部分，但其作用可能是允许性的。哌唑嗪和育亨宾均能拮抗i.c.v.吗啡对肝脏GSH的作用，再加上明显不存在外周儿茶酚胺能机制，表明肾上腺素能与i.c.v.吗啡作用的相互作用也是中枢起源的。因此，本研究结果表明，吗啡的中枢作用可导致肝脏GSH减少，且该作用不是由外周儿茶酚胺能机制介导的。
