XEN-DORPHINS--A NEW OPIOID SYSTEM

XEN-DORPHINS——一种新的阿片类药物系统

• 批准号: 2898189
• 负责人: SRINIVASA R NAGALLA
• 金额: $ 9.84万
• 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/2898189
• 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.

了解阿片类药物介导的重要效应，如止痛 而容忍和依赖等复杂的行为影响 阿片受体的分子克隆极大地促进了 和配基。有证据表明，多种阿片受体形式 (除了四个克隆的哺乳动物受体)和它们的 内源性配体参与阿片类药物介导的效应。我们 已经开始关闭这些新的阿片样药 (多肽前体)分子及其潜在的受体， 最初是在两栖动物中利用相对较高的水平 表示结束策略的表达式，并提供 CDNA和序列信息将有助于其 哺乳动物的特征。 我们已经分离出两个新的两栖类阿片样前亲体- 不同于脑啡肽和前强啡肽的激素 前体和一种新的阿片受体，可以作为同源物 这些新配体的受体。新的非洲爪哇受体 分离与Ze3n-dlephins结合，并了解阿片配体。 利用两栖类受体序列，我们已经分离出 从小鼠脑中提取的哺乳动物激素属于这一新的 受体亚家族，这与已知的四个 哺乳动物的受体。新的阿片肽(Xen- 吗啡)与已知阿片受体Qld结合。可以生产 强效阿片类药物对小鼠的镇痛作用。 我们的假设是这些小说的哺乳动物同源物 阿片样前激素及其同源受体在 在介导阿片类药物效应中的重要作用，如镇痛和 宽容。为了解决我们的假设，我们提出了以下建议 具体目标： 1)确定两栖动物Zen-dlephin的配基特异性 受体；这一信息将使我们的哺乳动物受体 新亚家族的特征。 2)克隆哺乳动物受体的全长形式 利用小鼠脑内部分受体片段并确定其 配基的特异性和分布 3)进一步研究阿片介导的镇痛作用。 在小鼠体内使用Xen-dleins。具体地说，我们将检查 新型阿片肽产生耐受性或调节耐受性 由吗啡产生。这种新型阿片类药物的表征 配体-受体家族(Xen-dformins)将进一步促进我们的 对阿片类药物介导的分析和耐受性的理解 反过来又为疼痛和药物滥用管理提供了更好的工具。