MECHANISM OF AN OPIOID, ORPHANIN FQ, ON COLONIC FUNCTION

描述(改编自申请人的摘要)：一部新奇的、内生的 阿片肽，孤儿FQ/伤害素(OFQ/N)及其受体ORL-1， 已经从大脑中分离出来。OFQ/N和ORL-1蛋白和mRNA广泛存在 在中枢神经系统和外周表达。OFQ/N具有复杂性 药理学，并已被证明要么是止痛的，要么是痛敏的 啮齿动物皮肤疼痛的化验。OFQ/N在内脏痛中的作用尚不清楚。 我们的初步研究表明，与吗啡或其他阿片类药物一样，OFQ/N 化合物，显著抑制体内结肠运输，并刺激 体外培养的结肠平滑肌。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 缺乏滥用和成瘾的阿片类药物，如吗啡或 芬太尼。 这项提案的总体目标是评估OFQ/N在以下方面的作用 内脏疼痛和结肠运动。我们的假设是OFQ/N是一个 这些过程的内源性主调制子。同时利用人类和 小鼠物种，我们建议通过以下方式来检验这一假设 具体目标：(1)操作上确定生物体内的位置(S) 其中OFQ/N负责调节结肠活动并评估相互作用 OFQ/N与体内阿片类药物之间的关系；将功能研究与 结构研究将定位OFQ/N及其受体的表达 Orl-1mRNA和多肽在小鼠和人结肠中的表达；(2)由于5-羟色胺已被 作为一种重要的神经递质参与胃肠道的控制 运动和内脏感觉，我们将研究5-羟色胺在 OFQ/N对人和小鼠结肠功能的作用机制， (3)我们将率先使用小鼠来测试内脏疼痛和使用 本实验旨在探讨OFQ/N在调节内脏痛中的作用。 利用ORL-1受体基因敲除动物进行这种新的内脏疼痛试验。 拟议的研究将在以下方面提供新的临床相关数据 新的内源性阿片类药物可能导致止痛药的开发 减少胃肠道副作用。

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.