EFFECT OF OPIOIDS AND OTHER DRUGS IN A MODEL CIRCADIAN SYSTEM

阿片类药物和其他药物在昼夜节律系统模型中的作用

• 批准号: 6237947
• 负责人: ROBERT F O'DEA
• 金额: $ 8.62万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-03-10 至 1998-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6237947
• 关键词: G protein; acyltransferase; adenylate cyclase; biological signal transduction; carbachol; chickens; circadian rhythms; clonidine; cyclic AMP; dynorphins; endogenous opioid; enzyme activity; forskolin; gene expression; hormone biosynthesis; melatonin; messenger RNA; methylation; morphine; norepinephrine; opioid receptor; pain; pharmacology; pineal body; posttranslational modifications; radiation sensitivity; serotonin; tissue /cell culture; vasoactive intestinal peptide; western blottings

The avian pinealocyte model is a novel system in which to explore the linkage between environmental or pharmacologic stimuli and hormone synthesis. Unlike the mammalian pineal, the avian gland is inherently photosensitive and rhythmic in its production of melatonin, expresses these characteristics either in vivo or in vitro and responds to light or catecholamines (alpha2 agonists) with an acute suppression of melatonin synthesis. This acute, inhibitory effect should also be produced by agents, such as opioid and muscarinic agonists, which disrupt cyclic AMP synthesis by mechanisms which involve the G-i class of GTP-binding proteins. Melatonin, a hormone which has anti-reproductive activity in numerous species, has also been shown to modify the analgesic responses to various opioid agents, suggesting that melatonin may be an endogenous modifier of opioid receptor activity. The primary hypothesis underlying this proposal is that the melatonin synthetic pathway is a logical target for pharmacologic agents which may exert feedback, inhibitory control on melatonin production, such as opioids. In this proposal, the effects of opioids and other related pharmacologic agents will be examined on pineal melatonin production, serotonin-N-acetyltransferase activity, cyclic AMP synthesis and light-dependent changes in G-protein subunit methylation, distribution and expression. In conclusion, as the avian pinealocyte model is both endogenously rhythmic and photosensitive, the investigations outlined in this proposal will determine whether opioid agonists and related compounds alter the pineal's acute biochemical responses and circadian behavior. As such, these studies will enhance our understanding of two critical physiological processes, response to pain and biological rhythmicity.

鸟类松果体细胞模型是一个新的系统，在其中探索 环境或药物刺激与激素之间的联系 合成. 与哺乳动物的松果体不同，鸟类的松果体 光敏和节奏的褪黑激素的生产，表达 这些特性在体内或体外，并响应于光或 具有褪黑激素急性抑制作用的儿茶酚胺（α 2激动剂） 合成. 这种急性的抑制作用也应该由以下物质产生： 破坏环AMP的药物，如阿片样物质和毒蕈碱激动剂 通过涉及G-i类GTP结合的机制合成 proteins. 褪黑激素，一种在哺乳动物中具有抗生殖活性的激素， 许多物种，也被证明可以改变镇痛反应 各种阿片类药物，这表明褪黑激素可能是内源性的， 阿片受体活性的调节剂。 这一提议的主要假设是， 合成途径是药理学试剂合理的靶点，其可以 对褪黑激素的产生施加反馈、抑制控制，例如 阿片类药物 在这项建议中，阿片类药物和其他相关药物的影响 将检查药理学试剂对松果体褪黑激素产生的影响， 降钙素-N-乙酰转移酶活性、环AMP合成和 光依赖性G蛋白亚基甲基化变化，分布 和表达。 总之，由于禽类松果体细胞模型既内源性地 有节奏和感光性，这项建议中概述的调查 将确定阿片激动剂和相关化合物是否改变了 松果体的急性生化反应和昼夜节律行为。 因此，在本发明中， 这些研究将加深我们对两个关键问题的理解， 生理过程，对疼痛的反应和生物节律。