OPIATE RECEPTOR PHARMACOLOGY
阿片受体药理学
基本信息
- 批准号:6378250
- 负责人:
- 金额:$ 11.86万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 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
项目摘要
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.
鸦片类药物对于治疗疼痛很重要,但它们的滥用是一个主要的健康问题。了解阿片类药物的作用对于临床合理使用阿片类药物和开发潜在的滥用治疗方法至关重要。阿片剂和阿片肽通过一系列受体发挥作用,其中一些已经被克隆。对这些受体在组织培养中的作用的研究已经提供了关于它们的生物化学的重要信息。然而,这些进步现在需要被纳入行为系统。最近使用反义方法的工作证实了克隆的阿片受体在阿片类药物药理学中的重要性。反义技术可以被用来选择性地针对单个外显子,从而允许检查剪接变体。使用这种针对编码Mu受体的MOR-1克隆的反义定位方法,我们发现吗啡及其极强的代谢物吗啡-6β-葡萄糖醛酸苷(M6G)的选择性不同,这意味着它们通过不同的受体发挥作用。这一点现已在MOR-1基因敲除小鼠中得到证实。这些动物对吗啡不敏感,但对M6G保持敏感。海洛因和几种高度有效的临床止痛药也通过M6G受体发挥作用,这一补充观察加强了M6G受体的重要性。尽管在基因敲除的小鼠中,吗啡处于不活动状态,但海洛因仍然具有完全的止痛活性。因此,M6G受体可能是一种新的海洛因受体。这一概念为未来对MU阿片系统的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名为孤儿FQ或伤害素的新多肽的发现。这些药物具有复杂的药理作用,我们将对其进行更详细的探讨。最后,先前的工作已经证实,西格玛受体激活了中枢神经系统中一个强大的抗阿片系统。这一系统导致了某些物种对止痛的敏感性不同。我们最近克隆了小鼠Sigma受体,并计划利用它通过反义和其他方法在分子水平上更好地了解这一系统。
项目成果
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GAVRIL W PASTERNAK其他文献
GAVRIL W PASTERNAK的其他文献
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