OPIOID DELTA SUBTYPES--CORRELATION IN VITRO AND IN VIVO

拟议工作的具体目标是：(A)直接确定 脑和其他组织中阿片受体亚型的研究 全脑控制膜中的放射性配基结合技术 用选择性和不可逆配体处理的膜，In 来自不同品系的小鼠的膜，据报道显示 阿片受体(例如，Mu受体)群体的差异 CXBK缺陷小鼠)，以及特定脑区的膜；(B) 调查在相互作用的调节方面可能的差异 受体亚型及其各自的效应器系统 在鸟嘌呤核苷酸、阳离子存在下的放射性配基结合 (或两者兼而有之)，或在体外或体外用百日咳毒素预处理后 活体；(C)使用放射性配基结合技术 重复/连续耐受和超敏感的机制 大脑暴露于对阿片三角洲具有选择性的化合物 受体亚型，以及(D)在 测定NG 108-15中腺苷酸环化酶活力的效应系统 细胞。这种方法将提供对阿片三角洲亚型的洞察， 以及它们可能与大量数据相关的机制 在体内积累，并可能在建立潜在的 Delta亚型选择性药物的治疗作用。

The specific goals of the proposed work are to (a) directly identify opioid delta receptor subtypes in brain and other tissues using radioligand binding techniques in wholebrain control membranes, in membranes pretreated with selective and irreversible ligands, in membranes from different strains of mice which have been reported to show differences in populations of opioid receptors (e.g., the mu-receptor deficient CXBK mouse), and in membranes from specific brain regions; (b) investigate possible differences in the regulation of interactions of the receptor subtypes with their respective effector systems by evaluation of radioligand binding in the presence of guanine nucleotides, cations (or both), or following pretreatment with pertussis toxin in vitro or in vivo; (c) use radioligand binding techniques to evaluate possible mechanism of tolerance and supersensitivity following repeated/continuous exposure of the brain to compounds with selectivity for the opioid delta receptor subtypes, and (d) use some of the above approaches in an effector system by measuring adenylyl cyclase activity in NG 108-15 cells. Such approaches will provide insights into opioid delta subtypes, and their mechanisms which may correlate with substantial data accumulated in vivo, and may be important in establishing the potential therapeutic utility of delta subtype selective drugs.