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解毒方法的可行性的数据，该方法使用极低剂量的纳洛酮预处理来减少吗啡依赖大鼠的戒断症状。药物戒断管理往往是阿片类药物依赖患者治疗的第一步。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，在戒毒方案中使用阿片拮抗剂（即纳洛酮，纳洛酮）已被引入以急剧减少戒断持续时间，但代价是需要重度镇静甚至麻醉的症状强度大大增加。由此产生的严重的医疗并发症阻碍并限制了这种方法的使用。另一方面，关于极低剂量阿片拮抗剂的镇痛和降低依赖性特性的实验证据指出了在解毒过程中使用这些拮抗剂药物的替代策略。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充分的描述，但这些变化背后的细胞基础直到最近才被描述。在戒断过程中，几个脑核团表现出立即早期基因表达（例如c-fos），其被用作神经元激活的标志物。此外，改变细胞内信使，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）已被证明阿片类药物戒断后，在中枢神经系统。本研究的具体目的是检验这一假设，即用极低剂量的阿片受体拮抗剂预处理阿片依赖大鼠改善戒断的行为和生化表达。目的I中的实验旨在检查纳洛酮预处理是否减少戒断的厌恶和躯体体征。为此，将根据良好描述的行为评分对退缩的行为表达进行评级。目的II将检查c-fos蛋白在已知在戒断后被激活的脑区域中的分布，以测试非常低剂量的纳洛酮预处理是否减少这些脑区域中c-fos的表达。最后，Aim III将使用蛋白质印迹分析来检查已知在戒断过程中增加的细胞内信使的水平，以确定这些在低剂量纳洛酮预处理后是否发生改变。收集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.