STUDIES OF THE OPIATE SYSTEM IN CHOLESTATIC LIVER DISEASE

阿片系统在胆汁淤积性肝病中的研究

• 批准号: 3840479
• 负责人: E A JONES
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3840479
• 关键词: cholestasis; clinical trials; disease /disorder model; drug administration routes; enkephalins; human subject; human therapy evaluation; human tissue; in situ hybridization; laboratory rat; liver disorder chemotherapy; naloxone; narcotic antagonists; northern blottings; opioid receptor; primary biliary cirrhosis; pruritis; receptor expression

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.

增加阿片系统功能活性的假设 有助于胆汁淤积的病理生理学正在接受测试 动物模型和人。使用纳洛酮客观监测系统 输液已被证明可以减少抓挠活动，独立于 8 名因以下原因而出现瘙痒的患者的全身运动增加了 26-96%： 原发性胆汁性肝硬化的单盲对照试验。在一个 双盲对照试验纳洛酮输注与 29 名瘙痒患者中有 24 名的抓挠活动减少，原因是 慢性胆汁淤积（p 小于 0.003）。这些发现证实了 阿片类药物系统在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），而且 内源性阿片类药物介导瘙痒。口语能力 生物可利用的阿片拮抗剂纳美芬提供长期控制 慢性胆汁淤积引起的瘙痒正在评估中。开放标签 针对 16 名患者的研究已经完成，取得了令人鼓舞的结果 双盲安慰剂对照研究已经启动。增加 抗伤害感受强烈暗示胆汁淤积中的阿片样张力 这是通过纳洛酮和下调立体选择性逆转的 胆管切除 (BDR) 大鼠脑内 mu-阿片受体，但大鼠没有 伴有急性肝细胞坏死。使用 Northern 印迹 前脑啡肽原 mRNA 已被证明明确表达于 BDR 大鼠的肝脏，但不是对照大鼠的肝脏。该表达式由 杂交组织化学位于增殖胆汁的细胞核中 导管细胞并与免疫组织化学阳性相关 甲硫脑啡肽染色。这些发现表明胎儿 肝脏合成阿片肽的能力在 胆汁淤积。