Very Low Naltrexone Treatment of Opiate Withdrawal

描述（由申请人提供）：本R21申请旨在收集有关新型阿片解毒方法可行性的数据，该方法使用极低剂量纳曲酮预处理来减少吗啡依赖大鼠的戒断症状。药物戒断管理通常是治疗阿片依赖患者的第一步。虽然已经采用了各种各样的解毒技术，但仍在继续寻找更有效的方法。最近，在解毒方案中使用阿片类拮抗剂（即纳曲酮，纳洛酮）已被引入，以急剧缩短戒断时间，但代价是大大增加了需要大量镇静甚至麻醉的症状强度。由此产生的严重并发症阻碍并限制了这种方法的使用。另一方面，极低剂量阿片类拮抗剂的镇痛和减少依赖特性的实验证据指出了在解毒期间使用这些拮抗剂药物的另一种策略。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描述出来。在戒断过程中，一些脑核表现出立即的早期基因表达（例如c-fos），这被用作神经元激活的标志。此外，中枢神经系统的细胞内信使，包括环磷酸腺苷（cAMP）依赖性蛋白激酶（PKA）和cAMP反应元件结合蛋白（CREB）在阿片类药物戒断后发生了变化。本研究的具体目的是验证极低剂量阿片拮抗剂预处理阿片依赖大鼠可改善戒断行为和生化表达的假设。在Aim I的实验被提议检查纳曲酮预处理是否减少戒断的厌恶和躯体迹象。为此，戒断的行为表现将根据一个描述良好的行为评分进行评分。Aim II将检查c-fos蛋白在已知停药后激活的脑区中的分布，以测试极低剂量纳曲酮预处理是否会减少这些脑区中c-fos的表达。最后，Aim Ill将使用western blot分析检测已知在停药期间增加的细胞内信使水平，以确定这些水平是否在低剂量纳曲酮预处理后发生改变。收集到的信息将为设计人体解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.