NEUTRAL ANTAGONISTS--FUNCTIONAL STUDIES

描述：（申请人摘要） 阿片类药物耐受性形成的神经元机制及其机制 几十年来，依赖性一直困扰着研究人员。 最近对A 新的药理学类别的化合物，称为中性拮抗剂， 表明这些化合物可以减弱激动剂产生的作用， 无法产生自己的影响。 此外，中性拮抗剂 似乎逆转了传统拮抗剂在体内产生的作用 和体外培养。 已经合成了一类生长抑素类似物， 包括选择性高亲和力阿片样物质配体，其可以作为 μ-阿片受体的中性拮抗剂。 目前有几份报告 表明这些所谓的中性拮抗剂逆转阿片类药物戒断 由传统的μ阿片受体拮抗剂产生。 的目标 建议的实验是评估行为和药理学 假定的中性拮抗剂在非依赖性和 吗啡依赖大鼠使用多种镇痛药物的辨别 程序. 通过提供第一个系统的行为评估， 中性拮抗剂的影响，这些研究可以从根本上改变 我们对阿片受体药理学的看法。 此外，委员会认为， 因为这些药物可以阻断μ阿片类药物的作用， 退出，这些实验的结果将是高度相关的 阿片类药物依赖的治疗

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.