BIOCHEMICAL CHARACTERIZATION OF OPIATE BINDING SITES

近年来在鸦片类药物中出现的最重要的概念之一 研究的是多个阿片受体的概念。最初提议的 作为“受体二元论”，这个概念现在已经扩展到一个整体 各种药理上定义的受体类别，包括Mu，Delta， 卡帕、西格曼和埃西隆。最近，Mu受体的两种亚型 已经被提出了。一个是MU2站点，对应于 吗啡选择性Mu受体以前的特征。另一种， MU1位点，代表在匀浆结合研究中首次发现的一个位点 它将阿片剂和阿片肽与类似的非常高的 亲和力。选择性MU1拮抗剂纳洛酮和纳洛酮有 事实证明，在确定MU1位点的药理作用方面非常有用， 例如，它们与椎管上止痛有关，但在 呼吸抑制或大多数身体依赖的迹象。这 应用提出了三个主要目标。第一个由 各类阿片类药物结合部位的表征。它 包括MU1、MU2、Delta的选择性结合分析的进展 和kappa位点，其次是它们的生化和药理作用 人物刻画。第二个目标是本地化 结合部位使用数字减影计算机化放射自显影。 这些研究将尝试定位MU1、MU2、Delta和kappa站点 也使用复杂的计算机分析大脑中的区域 作为它们突触前和突触后的分布。最后一个主要目标 涉及继续研究对一些 不可逆转的鸦片类药物。这些化合物的特征是结合 与其药理作用相关的研究及其选择性 行为。选定的化合物将被用作亲和标记 受体。最终，这样的研究应该会导致发展 为了更好地了解阿片剂的作用及其更多 在疼痛管理中的有效使用。

One of the most important concepts to emerge in recent years in opiate research is the concept of multiple opiate receptors. Originally proposed as "Receptor Dualism", this concept has now been expanded to a whole variety of pharmacologically-defined receptor classes, including mu, delta, kappa, sigman and epsilon. Most recently, two subtypes of mu receptors have been proposed. One, the mu2 site, corresponds to the morphine-selective mu receptor previously characterized. The other, the mu1 site, represents a site first recognized in homogenate binding studies which binds both opiates and opioid peptides with similar very high affinities. The selective mu1 antagonists naloxonazine and naloxazone have proven very helpful in defining the pharmacological role of mu1 sites, implicating them in supraspinal analgesia, for example, but not in respiratory depression or most signs of physical dependence. This application proposes three major aims. The first consists of the characterization of the various classes of opiate binding sites. It consists of the development of selective binding assays for mu1, mu2, delta and kappa sites, followed by their biochemical and pharmacological characterization. The second aim involves the localization of these binding sites using digital subtraction computerized autoradiography. These studies will attempt to localize mu1, mu2, delta and kappa sites using a sophisticated computer analysis to regions within the brain as well as their pre- versus post-synaptic distributions. The last major aim involves continuation of studies on the characterization of a number of irreversible opiates. These compounds will be characterized in binding studies and their selectivity correlated with their pharmacological actions. Selected compounds will be utilized as affinity labels for the receptor. Ultimately, studies such as these should lead to the development to a better understanding of the actions of opiates and their more effective use in the management of pain.