NON-OPIOID NEUROBIOLOGY OF OPIOID DEPENDENCE

本节包括一系列临床研究，旨在测试 关于鸦片剂依赖和戒断的假设 项目1-3的临床前工作。拟议的研究计划将 检查：l）临床阿片类药物的自发戒断 解毒研究，和2）纳洛酮促阿片类药物戒断， 一个重复的挑战模式。兴奋性氨基酸对 阿片类药物的戒断将首先与美沙芬进行研究， 一种广泛使用的非阿片类镇咳药， 神经传递的临床前研究，并已显示试点疗效 用于治疗鸦片戒断基于以下的临床前发现： 改变的钙通道浓度和钙相关的神经传递 在阿片类药物依赖的大鼠脑内，我们将研究抗戒断作用， 尼莫地平是一种中枢作用钙通道阻滞剂， 在试点研究中显示出了希望。阿片类药物的替代方法 解毒将测试是否重复施用α-2 肾上腺素能拮抗剂育亨宾对美沙酮依赖患者的作用 美沙酮停药时阿片类药物戒断的严重程度， 我们最近在实验室动物中进行的一项研究表明， 临床前组。

This section includes a series of clinical studies aimed to test hypotheses concerning opiate dependence and withdrawal generated by the preclinical work in Projects 1-3. The proposed program of research will examine: l) spontaneous opiate withdrawal in clinical opiate detoxification studies, and 2) naloxone-precipitated opiate withdrawal in a repeated challenge paradigm. The excitatory amino acid contribution to opiate withdrawal will be studied initially with dextromethorphan, a widely used non-opioid antitussive which inhibits excitatory amino acid neurotransmission in pre-clinical studies, and has shown pilot efficacy for the treatment of opiate withdrawal. Based on preclinical findings of altered calcium-channel concentration and calcium-linked neurotransmission in rat brain during opiate dependence, we will study the anti-withdrawal efficacy of nimodipine, a centrally-acting calcium channel blocker which has shown promise in pilot studies. An alternative approach to opiate detoxification will test whether repeated administration of the alpha-2 adrenergic antagonist yohimbine to methadone-dependent patients attenuates the severity of opiate withdrawal when methadone is discontinued, as suggested by a recent study in laboratory animals conducted by our preclinical group.