GASTROINTESTINAL CONTROL BY NEUROPEPTIDES

这项申请代表了对三个重要的 参与消化系统调节的神经肽系统和 其他内脏器官。调查的重点将是阿片肽， 速激肽(P物质、K物质等)和缩胆囊素 (CCK)。贯穿始终的重点是对神经肽机制的理解 与它们的药理作用，生理作用， 和生化特性。 中心假说是神经肽在感觉神经和 大脑、脊髓和外周的运动通路调节 胃肠道、膀胱的生理活动， 血管和其他内脏器官。具体的监管事件 由单个神经肽启动或调节的反映神经递质的 多种受体亚型在多个解剖部位的作用 通过多种分子形式并涉及与其他分子的多种相互作用 监管物质。因为神经肽的复杂性 行动和互动，需要一个全面的研究计划，以 同时解决多个生物水平的机制和 采用了多种实验方法。即使使用大型协作式 努力，并不是所有的多肽都可以一次研究。我们将重点关注三个方面 特殊的多肽类(阿片、速激肽和CCK)被认为是 参与内脏反射通路的感觉和运动成分。 之所以选择阿片肽，是因为它们被认为具有强大的 穴位作用对胃肠和膀胱运动的调节作用 大脑、脊髓和壁间部位，因为一系列 为他们的研究提供了药理工具(表1)。速激肽 已知在感觉和运动通路中都起作用，并在 多个水平的阿片类药物系统。胆囊素(CCK)含量很高 表现在与肠道相关的感觉和运动通路上，而且 似乎以特定的方式与阿片系统相互作用。

This application represents a systematic detailed study of three important neuropeptide systems involved in regulation of the digestive system and other visceral organs. The investigations will focus on opioid peptides, tachykinins (substance P, substance K and others), and cholecystokinin (CCK). Emphasis throughout is on understanding of neuropeptide mechanisms of action relevant to their pharmacological effects, physiological roles, and biochemical characteristics. The central hypothesis is that neuropeptides function in both sensory and motor pathways in the brain, spinal cord and periphery to regulate physiological activity of the gastrointestinal tract, urinary bladder, blood vessels, and other visceral organs. The specific regulatory events initiated or modulated by individual neuropeptides reflect neurotransmitter actions at multiple receptor subtypes in multiple anatomical sites mediated by multiple molecular forms and involving multiple interactions with other regulatory substances. Because of the complexities of the neuropeptide actions and interactions, a comprehensive research program is required that simultaneously addresses mechanisms at multiple biological levels and employs multiple experimental approaches. Even with a large collaborative effort, not all peptides can be studied at once. We will focus on three specific peptide groups (opioids, tachykinins and CCK) thought to be involved in both sensory and motor components of visceral reflex pathways. Opioid peptides were chosen because they are known to exert powerful regulatory effects on gastrointestinal and bladder motility by actions at brain, spinal cord and intramural sites and because an array of pharmacological tools in available for their study (Table 1). Tachykinins are known to function in both sensory and motor pathways and to interact at multiple levels with opioid systems. Cholesystokinin (CCK) is heavily represented in sensory and motor pathways relevant to the gut and also appears to interact in specific ways with opioid systems.