STUDIES OF THE OPIATE SYSTEM IN CHOLESTATIC LIVER DISEASE

阿片系统功能活动增加的假说 有助于胆汁淤积的病理生理学正在测试中， 采用纳洛酮客观监测系统， 输注已经显示出降低抓挠活动， 8例瘙痒症患者的全身运动减少26-96%， 原发性胆汁性肝硬化的单盲对照试验。中 双盲对照试验纳洛酮输注与 29例瘙痒患者中有24例的抓挠活动减少， 慢性胆汁淤积症（P <0.003）。这些发现证实了 阿片系统在皮肤瘙痒症发病机制中的作用 胆汁淤积，并表明，不仅阿片类药物，如吗啡， 内源性阿片样物质介导瘙痒。口语能力 生物可利用的阿片拮抗剂纳美芬提供长期控制 正在评估慢性胆汁淤积的瘙痒。一项开放标签 在16名患者中进行的研究已经完成，结果令人鼓舞， 已启动双盲安慰剂对照研究。增加 抗伤害性感觉强烈提示胆汁淤积中的阿片样张力 纳洛酮立体选择性逆转， 胆管切除（BDR）大鼠脑μ阿片受体，但无大鼠 急性肝细胞坏死使用北方印迹 前脑啡肽原mRNA已被证明是明确表达， BDR大鼠的肝脏，而不是对照组。这种表达是由 增殖期胆汁细胞核的杂交组织化学 免疫组化染色阳性 甲硫氨酸脑啡肽染色。这些发现表明，胎儿 肝脏合成阿片肽的能力在 胆汁淤积

The hypothesis that increased functional activity of the opioid system contributes to the pathophysiology of cholestasis is being tested in animal models and man. Using an objective monitoring system naloxone infusions have been shown to decrease scratching activity independent of gross body movements by 26-96% in 8 patients with pruritus due to primary biliary cirrhosis in a single blinded controlled-trial. In a double blind controlled trial naloxone infusions were associated with a decrease in scratching activity in 24 of 29 patients with pruritus due to chronic cholestasis (p less than 0.003). These findings confirm a role for the opioid system in the pathogenesis of the pruritus of cholestasis and suggest that not only opiates, like morphine, but also endogenuous opioids mediate pruritus. The ability of the orally bioavailable opiate antagonist nalmefene to provide long-term control of the pruritus of chronic cholestasis is being evaluated. An open label study in 16 patients has been completed with encouraging results and a double-blind placebo-controlled study has been initiated. Increased opiatergic tone in cholestasis is strongly suggested by anti-nociception that is stereoselectively reversed by naloxone and down regulation of brain mu-opioid receptors in bile duct resected (BDR) rats, but no rats with acute hepatocellular necrosis. Using Northern blots preproenekephalin mRNA has been shown to be unequivocally expressed in livers of BDR rats but not controls. This expression was shown by the hybridization histochemistry to be in the nuclei of proliferating bile ductular cells and was associated with positive immunohistochemical staining for met-enkephalin. These findings indicate that the fetal ability of the liver to synthesize opioid peptides is regained during cholestasis.