XEN-DORPHINS--A NEW OPIOID SYSTEM

XEN-DORPHINS——一种新的阿片类药物系统

• 批准号: 2393487
• 负责人: SRINIVASA R NAGALLA
• 金额: $ 9.93万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-08-01 至 2002-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2393487
• 关键词: analgesia; drug abuse chemotherapy; drug interactions; endogenous opioid; endorphins; genetic library; hormone regulation /control mechanism; in situ hybridization; laboratory mouse; molecular cloning; northern blottings; nucleic acid probes; nucleic acid sequence; opioid receptor; pain threshold; peptide hormone biosynthesis; polymerase chain reaction; receptor binding; receptor expression

Understanding important opioid-mediated effects such as analgesia and complex behavioral effects like tolerance and dependence has been greatly facilitated by molecular cloning of opioid receptors and ligands. Evidence suggest that multiple opioid receptor forms (besides the four cloned mammalian receptors) and their endogenous ligands are involved in opioid-mediated effects. We have initiated the closing of these new opioid prototypic (polypeptide precursors) molecules and their potential receptors, initially in amphibians to take advantage of the relative high levels of expression that cacilitates closing strategies and provides cDNAs and sequence information that will facilitate their characterization in mammals. We have isolated two novel amphibian opioid-like pre-pro- hormones that are distinct from the enkephalin and prodynorphin precursors and a new opioid receptor, that may act as a cognate receptor for these new ligands. The new Xenopus receptor isolated binds to Ze3n-dorphins and to know opioid ligands. Using the amphibian receptor sequence, we have isolated the mammalian hormolog from mouse brain that belongs to this new receptor subfamily, and that is distinct from the four known mammalian receptors. The new opioid-like peptides (Xen- dorphins) bind to known opioid receptors Qld. can produce potenent opioid medicated analgesia in mice. It is our hypothesis that the mammalian homologs of these novel opioid-like prohormones and their cognate receptors play an important role in mediating opioid effects such as analgesia and tolerance. To address our hypothesis we propose the following specific aims: 1) To define the ligand specificity of the amphibian Zen-dorphin receptor; this information will facilitate our mammalian receptor characterization of the new subfamily. 2) To clone the full length form of the mammalian receptor from mouse brain using the partial receptor fragment and to define its ligand specificity and distribution 3) To further characterize the opioid mediated analgesia induced by Xen-dorphins in mice. Specifically, we will examine if the novel opioid-like peptides produce tolerance or modulate tolerance produced by morphine. characterization of this novel opioid ligand-receptor family (Xen-dorphins) will further our understanding of the opioid mediated analygesia and tolernace and in turn provide better tools for pain and drug abuse management.

了解重要的阿片类药物介导的作用，如镇痛 以及复杂的行为效应如耐受性和依赖性 阿片受体的分子克隆 和配体。 有证据表明多种阿片受体形式 （除了四种克隆的哺乳动物受体）及其 内源性配体参与阿片样物质介导的作用。 我们 已经开始关闭这些新的阿片样物质原型， （多肽前体）分子及其潜在受体， 最初是在两栖动物中， 的表达，cacilitates关闭策略，并提供 cDNA和序列信息，这将有助于他们 哺乳动物的特征。 我们已经分离出两种新的两栖类阿片样前体， 与脑啡肽和强啡肽原不同的激素 前体和一种新的阿片受体，可能作为同源物 这些新配体的受体。 新的爪蟾受体 分离的结合Ze 3 n-多芬和已知的阿片样物质配体。 利用两栖动物受体序列，我们分离出了 来自小鼠大脑的哺乳动物激素，属于这种新的 受体亚家族，这是不同于四个已知的 哺乳动物受体 新的阿片样肽（Xen- dorphins）与已知的阿片受体Qld结合。可以产生 小鼠中有效的阿片类药物镇痛作用。 我们的假设是，这些新的哺乳动物同源物 类阿片样激素原及其同源受体发挥作用， 在介导阿片样物质作用如镇痛和 宽容 为了解决我们的假设，我们提出以下建议 具体目标： 1)为了确定两栖动物Zendorphin的配体特异性， 受体;这些信息将有助于我们的哺乳动物受体 新家族的特征。 2)为了克隆哺乳动物受体的全长形式， 小鼠大脑使用部分受体片段，并确定其 配体特异性和分布 3)为了进一步表征阿片介导的镇痛诱导 被异多芬注射到小鼠体内 具体来说，我们将研究 新的阿片样肽产生耐受性或调节耐受性 吗啡产生的。 这种新型阿片类药物的特征 配体-受体家族（Xen-dorphins）将进一步促进我们的研究。 了解阿片介导的分析和耐受， 反过来又为疼痛和药物滥用管理提供更好的工具。