PHYSIOLOGY AND PHARMACOLOGY OF OPIOIDS IN BRAIN

脑中阿片类药物的生理学和药理学

• 批准号: 2443457
• 负责人: Carl R. Lupica
• 金额: $ 12.94万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-07-01 至 2000-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2443457
• 关键词: biological signal transduction; calcium channel; cholecystokinin; electrophysiology; endogenous opioid; gamma aminobutyrate; hippocampus; inhibitor /antagonist; interneurons; laboratory rat; neural transmission; neurochemistry; neuropeptides; nitric oxide; opioid receptor; periaqueductal gray matter; stimulant /agonist; tissue /cell culture; voltage gated channel

Opioids are known to have important behavioral and physiological actions that are mediated by interactions with neurons in the central nervous system. However, while the behavioral actions of the opioids, including analgesia and euphoria, are well-known, the functional roles these molecules play as neuromodulators in the mammalian brain remain poorly understood. The following experiments will evaluate the actions of opioids, acting at pharmacologically defined mu-, delta- and kappa-opioid receptor subtypes, as modulators of synaptic transmission in the CA1 and dentate gyrus regions of the hippocampus, and in another brain region known as the periaqueductal gray. The experiments described in this proposal will utilize whole-cell patch clamp electrophysiological techniques to examine the effects of opioids on individual neurons in rat brain slice preparations. The first set of experiments will focus on the mechanisms through which mu-, delta-, and kappa-opioid receptor agonists act to decrease evoked and spontaneous synaptic transmission in the hippocampal slice. In particular, these experiments will examine the contributions made by distinct voltage-dependent calcium channels, intracellular calcium stores, and nitric oxide in supporting synaptic transmission and the modulation of this process. The second set of experiments will determine the effects of opioid agonists directly on subpopulations of gamma-aminobutyric acid (GABA)-containing neurons (interneurons) in the CA1 region of the hippocampus, and the cellular mechanisms these receptors utilize to affect these cells. These experiments will be aided through the use of differential interference contrast microscopy to identify these neurons in living brain slices. The third set of experiments will determine what mechanisms account for the ability of certain non-opioid peptides to attenuate the behavioral and cellular actions of the opioids. Thus, we will determine the effects of the peptides cholecystokinin (CCK) and neuropeptide FF on neurons found in the hippocampus, and the periaqueductal gray. The investigations described in this grant proposal should improve our understanding of the specific receptor subtypes that the opioids act upon, the cellular mechanisms mediating their responses, the roles opioids may play as neuromodulators in the brain, and the mechanism of their interaction with other non-opioid peptides. in addition, since limbic structures like the hippocampus have been shown to participate in normal and abnormal behavioral states such as learning, epilepsy, and emotional behavior, and the periaqueductal gray has been shown to be important in mediating opioid analgesia, these studies may yield new insights as to the interaction between opioids and these phenomena.

阿片类药物已知具有重要的行为和生理作用。 它是通过与中枢神经中的神经元相互作用来调节的 系统。然而，虽然阿片类药物的行为行为，包括 止痛和快感，是众所周知的，这些功能作用 分子发挥作用，哺乳动物大脑中的神经调节器仍然很弱 明白了。下面的实验将评估 阿片类药物，作用于药理学定义的Mu-、Delta-和Kappa-阿片 受体亚型，作为CA1和CA1区突触传递的调节器 海马齿状回区域，以及在另一个大脑区域 被称为中脑导水管周围灰质。本文件中描述的实验 方案将利用全细胞膜片钳电生理 阿片类药物对大鼠单个神经元影响的检测技术 脑片准备。第一组实验将集中在 U-阿片受体激动剂、β-阿片受体激动剂和kappa-阿片受体激动剂的作用机制 减少诱发的和自发的突触传递 海马片。特别是，这些实验将检验 不同的电压依赖性钙通道的贡献， 支持突触的细胞内钙储存和一氧化氮 这一过程的传输和调制。第二套 实验将直接确定阿片激动剂对 γ-氨基丁酸(GABA)神经元亚群 (中间神经元)在海马区CA1区，以及细胞 这些受体用来影响这些细胞的机制。这些 实验将通过使用差分干涉得到帮助 对比显微镜在活体脑片中识别这些神经元。这个 第三组实验将确定是什么机制解释了 某些非阿片肽能够减弱行为和 阿片类药物的细胞活动。因此，我们将确定 胆囊素(CCK)和神经肽FF对大鼠神经元的影响 海马体和中脑导水管周围灰质。所描述的调查 在这项赠款提案中，应该提高我们对具体 阿片类药物作用的受体亚型，细胞机制 阿片类药物作为神经调节剂可能扮演的角色 以及它们与其他非阿片类药物相互作用的机制 多肽。此外，由于海马体等边缘结构 被证明参与正常和异常的行为状态，例如 学习、癫痫和情绪行为，以及中脑导水管周围灰质 已被证明在介导阿片类止痛方面很重要，这些 研究可能会对阿片和阿片之间的相互作用产生新的见解 这些现象。