OPIATE RECEPTOR PHARMACOLOGY

阿片受体药理学

• 批准号: 6378250
• 负责人: GAVRIL W PASTERNAK
• 金额: $ 11.86万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-08-01 至 2004-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6378250
• 关键词: analgesia; antisense nucleic acid; chemical binding; cyclic AMP; drug tolerance; glucuronides; heroin; laboratory mouse; laboratory rat; molecular cloning; molecular site; morphine; narcotic antagonists; neuropharmacology; nitric oxide; opiate alkaloid; opioid receptor; pharmacogenetics; protein isoforms; protein protein interaction; protein structure function; receptor binding; receptor expression; second messengers; tissue /cell culture

Opiates are important for the treatment of pain, but their abuse presents a major health proglem. Understanding opioid actions is crucial to their rational use clinically and the development of potential treatments for abuse. Opiates and the opioid peptides act through a family of receptors, of which a number have been cloned. Studies on the actions of these receptors carried out in tissue culture have provided important information regarding their biochemistry. However, these advances now need to be taken into behavioral systems. Recent work using antisense approaches has confirmed the importance of the cloned opioid receptors in opioid pharmacology. Antisense techniques can be used to selectively target individual exons, permitting the examination of splice variants. Using this antisense mapping approach against the MOR-1 clone, which encodes a mu receptor, we found different selectivity profiles for morphine and its extremely potent metabolite morphine-6beta-glucuronide (M6G), implying that they act through distinct receptors. This has now been confirmed in MOR-1 knockout mice. These animals are insensitive to morphine, but retain their sensitivity to M6G. The importance of this M6G receptor is enhanced by the additional observations that heroin and several highly potent clinical analgesics also act through the M6G receptor. Despite the inactivity of morphine in the knockout mice, heroin retains its full analgesic activity. Thus, the M6G receptor might be considered a new heroin receptor. This concept provides important insights into future studies of the mu opioid system. Another member of the opioid receptor family has also proven very interesting. The orphan opioid receptor has led to the identification of a new series of peptides termed orphanin FQ or nociceptin. These agents have a complex pharmacology which will be explored in further detail. Finally, prior work has established that the sigma receptor activates a potent anti-opioid system within the central nervous system. This system is responsible for variations in analgesic sensitivity among some species. We recently cloned the murine sigma receptor and plan to utilize it to gain a better understanding at the molecular level of this system through antisense and other approaches.

阿片类药物对于治疗疼痛很重要，但他们的虐待表现出主要的健康状况。 了解阿片类药物的作用对于在临床上的合理使用以及对滥用的潜在治疗方法的发展至关重要。 阿片类药物和阿片类肽通过一个受体家族作用，其中许多受体被克隆。 关于这些受体在组织培养中进行的作用的研究提供了有关其生物化学的重要信息。 但是，现在需要将这些进步带入行为系统。 最近使用反义方法的工作证实了克隆的阿片类药物受体在阿片类药理学中的重要性。 反义技术可用于选择性地靶向单个外显子，从而检查剪接变体。 使用编码MU受体的MOR-1克隆的反义映射方法，我们发现了吗啡的选择性谱及其极有效的代谢物吗啡-6beta-6beta---------------------------------------------------------------------葡萄糖醛酸（M6G）暗示它们通过不同的受体起作用。 现在已经在MOR-1淘汰小鼠中得到了证实。 这些动物对吗啡不敏感，但保持对M6G的敏感性。 通过其他观察结果，海洛因和几种高度有效的临床镇痛药也通过M6G受体起作用，增强了该M6G受体的重要性。 尽管敲除小鼠中吗啡的活动不活跃，但海洛因仍保留了其完整的镇痛活性。因此，M6G受体可能被认为是新的海洛因受体。这个概念为MU阿片类药物系统的未来研究提供了重要的见解。 阿片受体家族的另一个成员也非常有趣。 孤儿阿片受体已导致鉴定出称为孤立蛋白FQ或Nocteptin的新肽。 这些药物具有复杂的药理学，将进一步详细探讨。最后，先前的工作已经确定，Sigma受体在中枢神经系统中激活有效的抗阿片类系统。 该系统负责某些物种之间的镇痛敏感性变化。 我们最近克隆了鼠Sigma受体，并计划利用它通过反义和其他方法在该系统的分子水平上获得更好的了解。