Tariot P N, Sunderland T, Murphy D L, Cohen M R, Welkowitz J A, Weingartner H, Newhouse P A, Cohen R M
Prog Neuropsychopharmacol Biol Psychiatry. 1986;10(3-5):611-26. doi: 10.1016/0278-5846(86)90031-x.
In view of the reports of possible beneficial effects of naloxone in dementia, rationales and strategies for studying endogenous opiate systems are reviewed. Important considerations in the design and interpretation of clinical investigations using naloxone are also reviewed. The nature and distribution of endogenous opiate systems are summarized from an historical perspective. Endogenous opiate systems are distributed throughout the central nervous system and play important roles in a variety of brain functions, including memory and learning. In view of this, several rationales are evident for studying endogenous opiate systems in dementia, since it is a syndrome in which structures known to contain opiate systems are disturbed, functions modulated by opiate systems are disturbed, and other neurotransmitter systems (functionally linked to endogenous opiate systems) are disturbed. Different strategies for studying endogenous opiate systems are reviewed, including examination of body fluids and pharmacologic challenge studies. Naloxone hydrochloride, a competitive opiate receptor antagonist, is a commonly used pharmacologic agent. The design of a multidose naloxone study of 12 dementia patients is discussed, with reference to the pharmacokinetics, pharmacodynamics, and specificity of naloxone as well as to the nature of the dependent measures selected for this study. No cognitive benefit was observed in this study. Behavioral arousal was observed at naloxone doses, with more evident psychomotor retardation at higher doses. These findings are contrasted with the results of naloxone challenges in other studies. The varying effects of naloxone within and across populations can be conceptualized in terms of the basic and clinical considerations previously discussed. The importance of dose-finding studies is stressed for this and other drug trials.
鉴于有关纳洛酮对痴呆可能具有有益作用的报道，本文对研究内源性阿片系统的基本原理和策略进行了综述。同时也回顾了使用纳洛酮进行临床研究的设计和解读中的重要注意事项。从历史角度总结了内源性阿片系统的性质和分布。内源性阿片系统遍布中枢神经系统，在包括记忆和学习在内的多种脑功能中发挥重要作用。鉴于此，研究痴呆中的内源性阿片系统有几个明显的基本原理，因为痴呆是一种已知含有阿片系统的结构受到干扰、由阿片系统调节的功能受到干扰以及其他与内源性阿片系统功能相关的神经递质系统受到干扰的综合征。本文回顾了研究内源性阿片系统的不同策略，包括对体液的检测和药理学激发研究。盐酸纳洛酮是一种竞争性阿片受体拮抗剂，是常用的药理学试剂。本文讨论了一项针对12名痴呆患者的多剂量纳洛酮研究的设计，涉及纳洛酮的药代动力学、药效学和特异性，以及为本研究选择的相关测量指标的性质。本研究未观察到认知益处。在纳洛酮给药剂量下观察到行为唤醒，在较高剂量下精神运动迟缓更明显。这些发现与其他研究中纳洛酮激发试验的结果形成对比。纳洛酮在不同人群内部和之间的不同作用可以根据之前讨论的基本和临床因素来理解。强调了本研究及其他药物试验中剂量探索研究的重要性。
