EFFECT OF OPIOIDS AND OTHER DRUGS IN A MODEL CIRCADIAN SYSTEM

鸟类松果体细胞模型是一种新的探索 环境或药物刺激与激素之间的联系 综合。与哺乳动物的松果体不同，鸟类的腺体天生就是 在其产生褪黑素的光敏和节律性，表达 这些特性无论是在体内还是在体外都能对光或 儿茶酚胺(α2激动剂)对褪黑素的急性抑制作用 综合。这种剧烈的、抑制的效应也应该由 阿片类药物和毒扁豆碱激动剂等能破坏环磷酸腺苷的药物 涉及G-I类GTP结合机制的合成 蛋白质。褪黑素，一种在体内具有抗生殖活性的激素 许多物种，也已被证明可以改变止痛反应 对各种阿片类药物的作用，提示褪黑素可能是内源性的 阿片受体活性的修饰物。 支持这一提议的主要假设是褪黑素 合成途径是药理学药物的合理靶点，它可能 对褪黑激素的产生施加反馈、抑制控制，如 阿片类药物。在这项提案中，阿片类药物和其他相关药物的影响 将对松果体褪黑素的产生进行药理药物的检测， 5-羟色胺-N-乙酰转移酶活性、环磷酸腺苷合成和 G蛋白亚基甲基化、分布的光依赖性变化 和表情。 综上所述，由于鸟类松果体细胞模型既有内源性 节奏性和光敏性，这项提案中概述的研究 将决定阿片类激动剂和相关化合物是否会改变 松果体的急性生化反应和昼夜行为。因此， 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性。

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.