Very Low Naltrexone Treatment of Opiate Withdrawal

描述(由申请人提供)：本R21申请的目的是收集关于一种新的阿片类药物戒毒方法的可行性的数据，该方法使用极低剂量的纳曲酮预处理来减轻吗啡依赖大鼠的戒断症状。药物戒断管理通常是阿片类药物依赖患者治疗的第一步。虽然已经采用了广泛的戒毒技术，但仍在继续寻找更有效的方法。最近，在戒毒方案中使用阿片类拮抗剂(即纳曲酮、纳洛酮)可以大幅缩短戒断时间，但代价是症状强度大大增加，需要大量的镇静甚至麻醉。由此产生的严重医疗并发症阻碍并限制了这种方法的使用。另一方面，关于极低剂量阿片类拮抗剂的止痛和减少依赖特性的实验证据表明，在戒毒期间使用这些拮抗剂药物是一种替代策略。虽然阿片类药物戒断的行为表现已经在动物模型中得到了彻底的描述，但这些变化背后的细胞基础直到最近才被表征。一些大脑核团在戒断过程中表现出即刻的早期基因表达(如c-fos)，这被用作神经元激活的标志。此外，中枢神经系统戒断阿片后，细胞内信使的变化，包括环磷酸腺苷(CAMP)依赖的蛋白激酶(PKA)和cAMP反应元件结合蛋白(CREB)。本研究的具体目的是验证阿片依赖大鼠预先给予极低剂量阿片受体拮抗剂可改善戒断行为和生化表达的假说。Aim I的实验是为了检验纳曲酮预处理是否能减少戒断的厌恶和躯体迹象。为此，戒断的行为表达将根据描述良好的行为得分进行评级。目的II将检测c-fos蛋白在戒断后被激活的脑区的分布，以测试极小剂量的纳曲酮预处理是否减少这些脑区c-fos的表达。最后，Aim Ill将使用蛋白质印迹分析来检测在戒断过程中已知的细胞内信使水平的增加，以确定这些信使在小剂量纳曲酮预处理后是否发生改变。收集到的信息将为设计人体戒毒试验提供必要的基础。

DESCRIPTION (provided by applicant): It is the intention of this R21 application to gather data regarding the feasibility of a novel opiate detoxification method, with the use of very low-dose naltrexone pretreatment to reduce withdrawal symptoms in morphine dependent rats. Pharmacological withdrawal management is often the first step in the treatment of opiate dependent patients. Although a wide range of detoxification techniques have been employed, there is a continuing search for more effective approaches. Recently, the use of opiate antagonists (i.e. naltrexone, naloxone) in detoxification protocols has been introduced to sharply decrease withdrawal duration, but at the cost of greatly increased symptom intensity requiring heavy sedation and even anesthesia. Resulting serious medical complications has discouraged and limited the use of this approach. On the other hand, experimental evidence on analgesic and dependence-reducing properties of very low doses of opiate antagonists points to an alternative strategy for the use of these antagonist drugs during detoxification. Although the behavioral manifestations of opiate withdrawal have been thoroughly described in animal models, the cellular bases underlying these changes have only recently been characterized. Several brain nuclei exhibit immediate early gene expression (e.g. c-fos), which is used as a marker of neuronal activation, in the course of withdrawal. Furthermore, alterations in intracellular messengers, including cyclic adenosine monophosphate (cAMP)-dependent protein kinases (PKA), and cAMP-response element-binding protein (CREB) have been shown following opiate withdrawal in the central nervous system. Specific purpose of this study is to test the hypothesis that pretreatment of opiate dependent rats with very-low doses of opiate antagonists ameliorates behavioral and biochemical expressions of withdrawal. Experiments in Aim I are proposed to examine whether naltrexone pretreatment reduces the aversive and somatic signs of withdrawal. To this end, behavioral expression of withdrawal will be rated according to a well-described score of behaviors. Aim II will examine the distribution of c-fos protein in brain regions known to be activated following withdrawal to test whether very low-dose naltrexone pretreatment diminishes the expression of c-fos in these brain areas. Finally, Aim Ill will use western blot analysis to examine levels of intracellular messengers known to be increased during withdrawal to determine whether these are altered following pretreatment with low-doses of naltrexone. The information collected will provide the necessary foundation for designing detoxification trials in humans.