OPIOID DELTA SUBTYPES--CORRELATION IN VITRO AND IN VIVO

拟议工作的具体目标是：（a）直接查明 阿片δ受体亚型在脑和其他组织中的应用 放射性配体结合技术在全脑控制膜， 用选择性和不可逆配体预处理的膜， 据报道，不同品系小鼠的细胞膜显示， 阿片受体群体的差异（例如，μ受体 缺陷型CXBK小鼠），和来自特定脑区域的膜;（B） 研究可能的差异，在相互作用的调节， 受体亚型及其各自的效应子系统的评价 在鸟嘌呤核苷酸、阳离子存在下的放射性配体结合 (or两者），或在体外或体内用百日咳毒素预处理后 （c）使用放射性配体结合技术来评估可能的 重复/连续用药后耐受和超敏反应的机制 大脑暴露于对阿片δ具有选择性的化合物 受体亚型，和（d）使用上述方法中的一些， 通过测量NG 108-15中腺苷酸环化酶活性的效应子系统 细胞 这些方法将提供对阿片δ亚型的深入了解， 以及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重要 δ亚型选择性药物的治疗效用。

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.