NEUTRAL ANTAGONISTS--FUNCTIONAL STUDIES

描述：(申请人摘要) 阿片类药物耐受发生的神经元机制 几十年来，研究人员一直在逃避依赖。最近对一项 新的药理类化合物，称为中性拮抗剂， 表明这些化合物可以减弱激动剂产生的影响，但 不能产生自己的效果。此外，中性拮抗剂 似乎逆转了传统拮抗剂在体内产生的效果 而且是在体外。合成了一类生长抑素类似物 包括选择性高亲和力阿片配体，可能是候选 阿片受体的中性拮抗剂。一些最新的报道说 表明这些所谓的中性拮抗剂逆转了阿片类药物的戒断 由传统的Mu阿片受体拮抗剂产生。的目标是 拟议的实验是为了评估行为和药理学 非依赖型和非依赖型中性拮抗剂的性质 吗啡依赖大鼠使用多种镇痛方法及药物辨别 程序。通过提供第一个系统的行为评估 中性拮抗剂的作用，这些研究可能从根本上改变 我们思考阿片受体药理学的方式。此外， 因为这些药物阻断了穆阿片类药物的作用，但不会沉淀 停用，这些实验的结果将与 阿片依赖的治疗。

DESCRIPTION: (Applicant's Abstract) The neuronal mechanisms underlying the development of opioid tolerance and dependence have eluded researchers for decades. Recent investigations of a novel pharmacological class of compounds, called neutral antagonists, indicate that these compounds may attenuate effects produced by agonists but fail to produce effects of their own. In addition, neutral antagonists appear to reverse the effects produced by traditional antagonists in vivo and in vitro. A class of somatostatin analogues has been synthesized that includes selective high-affinity opioid ligands that may be candidates as neutral antagonists for the mu-opioid receptor. A few current reports have indicated that these purported neutral antagonists reverse opiate withdrawal produced by traditional mu-opiate receptor antagonists. The goal of the proposed experiments is to evaluate the behavioral and pharmacological properties of the putative neutral antagonists in nondependent and morphine-dependent rats using a variety of analgesia and drug discrimination procedures. By providing the first systematic evaluation of the behavioral effects of neutral antagonists, these studies could radically alter the manner in which we think about opioid receptor pharmacology. Furthermore, because these drugs block the effects of mu opioids, but do not precipitate withdrawal, the findings of these experiments will be highly relevant to the treatment of opioid dependence.