MECHANISM OF AN OPIOID, ORPHANIN FQ, ON COLONIC FUNCTION

阿片类药物孤啡肽 FQ 对结肠功能的作用机制

• 批准号: 6259404
• 负责人: MILES L EPSTEIN
• 金额: $ 18.19万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-01 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6259404
• 关键词: bioassay; colon; gastrointestinal motility /pressure; gene targeting; human tissue; laboratory mouse; nociceptin; opioid receptor; pain; protein localization; serotonin

DESCRIPTION (Adapted from the Applicant's Abstract): A novel, endogenous opioid-like peptide, orphanin FQ/nociceptin (OFQ/N), and its receptor, ORL-1, have been isolated from brain. OFQ/N and ORL-1 protein and mRNA are widely expressed in the central nervous system and periphery. OFQ/N has a complex pharmacology and has been shown to be either analgesic or hyperalgesic in rodent assays of cutaneous pain. The role of OFQ/N in visceral pain is unknown. Our preliminary studies show that OFQ/N, like morphine or other opioid compounds, significantly inhibits colonic transit in vivo and stimulates colonic smooth muscle in vitro. More important, OFQ/N's actions are insensitive to opioid receptor antagonists such as naloxone. Thus, OFQ/N and its receptor ORL-1 may be novel therapeutic targets for the treatment of visceral pain which would lack the abuse and addiction liabilities of opioids such as morphine or fentanyl. The overall objective of this proposal is to evaluate the role of OFQ/N in visceral pain and colonic motility. Our hypothesis is that OFQ/N is an endogenous principal modulator of these processes. Utilizing both human and murine species, we propose to test this hypothesis through the following specific aims: (1) operationally identify the location(s) within the organism where OFQ/N acts to regulate colonic activity and evaluate the interactions between OFQ/N and opioids in vivo; correlate the functional studies with structural studies which will localize the expression of OFQ/N and its receptor ORL-1 mRNA and polypeptide in murine and human colon; (2) because 5-HT has been implicated as an important neurotransmitter involved in the control of GI motility and visceral sensation, we will examine 5-HT's involvement in the mechanism of action of OFQ/N on colonic function in human and murine tissue, (3) we will pioneer the use of the mouse in an assay of visceral pain and use this assay to evaluate the role of OFQ/N in modulating visceral pain by utilizing ORL-1 receptor knockout animals in this novel visceral pain assay. The proposed studies will contribute new and clinically relevant data on a novel endogenous opioid which could lead to the development of analgesics with reduced GI side effects.

描述（改编自申请人的摘要）：一种新颖的内源性的 阿片样肽，阿片肽FQ/痛敏肽（OFQ/N），及其受体，ORL-1， 从大脑中分离出来。OFQ/N和ORL-1蛋白和mRNA在人外周血中广泛表达， 在中枢神经系统和外周表达。OFQ/N具有复合物 药理学，并已被证明是镇痛或痛觉过敏， 皮肤疼痛的啮齿动物测定。OFQ/N在内脏痛中的作用尚不清楚。 我们的初步研究表明，OFQ/N，如吗啡或其他阿片类药物， 化合物，在体内显著抑制结肠运输，并刺激 离体结肠平滑肌。更重要的是，OFQ/N的行动是不敏感的， 阿片受体拮抗剂如纳洛酮。因此，OFQ/N及其受体 ORL-1可能是治疗内脏痛的新靶点， 没有阿片类药物如吗啡或吗啡的滥用和成瘾倾向， 芬太尼 本提案的总体目标是评估OFQ/N在以下方面的作用： 内脏疼痛和结肠蠕动我们的假设是，OFQ/N是 这些过程的内源性主要调节剂。利用人类和 鼠种，我们建议通过以下方式来验证这一假设 具体目标：（1）在操作上确定生物体内的位置 其中OFQ/N用于调节结肠活动并评估相互作用 OFQ/N和阿片类药物之间的关系;将功能研究与 定位OFQ/N及其受体表达的结构研究 ORL-1 mRNA和多肽在小鼠和人结肠中的表达;（2）由于5-HT已被 暗示作为一个重要的神经递质参与控制胃肠道 运动和内脏感觉，我们将检查5-HT的参与， OFQ/N对人和小鼠组织中结肠功能的作用机制， (3)我们将率先使用小鼠来检测内脏疼痛， 本试验旨在评价OFQ/N在调节内脏痛中的作用， 在这种新的内脏疼痛测定中使用ORL-1受体敲除动物。 拟议的研究将提供新的临床相关数据， 新的内源性阿片样物质，可能导致镇痛药的发展， 减少胃肠道副作用。