OPIATE RECEPTOR PHARMACOLOGY

阿片受体药理学

• 批准号: 2756682
• 负责人: GAVRIL W PASTERNAK
• 金额: $ 9.72万
• 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/2756682
• 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.

阿片类药物对治疗疼痛很重要，但滥用阿片类药物会造成重大的健康问题。 了解阿片类药物的作用对于临床合理使用和开发潜在的滥用治疗方法至关重要。 阿片类药物和阿片肽通过一个受体家族发挥作用，其中一些已经被克隆。 在组织培养中对这些受体的作用进行的研究提供了关于其生物化学的重要信息。 然而，这些进步现在需要纳入行为系统。 最近的工作使用反义方法证实了克隆阿片受体在阿片药理学中的重要性。 反义技术可用于选择性靶向单个外显子，允许检查剪接变体。 使用这种针对编码μ受体的莫尔-1克隆的反义作图方法，我们发现了吗啡及其极其有效的代谢物吗啡-6 β-葡糖苷酸（M6 G）的不同选择性概况，这意味着它们通过不同的受体起作用。 这已经在莫尔-1敲除小鼠中得到证实。 这些动物对吗啡不敏感，但对M6 G保持敏感。 这种M6 G受体的重要性被海洛因和几种高效临床镇痛药也通过M6 G受体起作用的额外观察结果所增强。 尽管吗啡在敲除小鼠中不起作用，但海洛因保留了其全部镇痛活性。因此，M6 G受体可能是一种新的海洛因受体。这一概念为μ阿片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被证明非常有趣。 孤儿阿片受体导致了一系列新的肽的鉴定，称为阿片肽FQ或伤害感受素。 这些药物具有复杂的药理学作用，将进一步详细探讨。最后，先前的工作已经确定，σ受体激活中枢神经系统内的有效抗阿片系统。 该系统负责某些物种之间镇痛敏感性的变化。 我们最近克隆了小鼠σ受体，并计划利用它来获得更好的理解，在分子水平上的这个系统，通过反义和其他方法。