PHYSIOLOGY AND PHARMACOLOGY OF OPIOIDS IN BRAIN

脑中阿片类药物的生理学和药理学

基本信息

批准号：
2120216
负责人：
Carl R. Lupica
金额：
$ 13.33万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
1992
资助国家：
美国
起止时间：
1992-07-01 至 2000-06-30
项目状态：
已结题

项目摘要

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.

众所周知，阿片类药物具有重要的行为和生理作用通过与中枢神经元的相互作用介导系统。然而，虽然阿片类药物的行为作用，包括镇痛和欣快感是众所周知的，它们的功能作用分子在哺乳动物大脑中作为神经调节剂的作用仍然很差明白了。以下实验将评估阿片类药物，作用于药理学定义的 mu-、delta- 和 kappa-阿片类药物受体亚型，作为 CA1 和突触传递的调节剂海马体的齿状回区域和另一个大脑区域称为导水管周围灰质。本文描述的实验该提案将利用全细胞膜片钳电生理学检查阿片类药物对大鼠个体神经元影响的技术脑切片制剂。第一组实验将集中于 mu-、delta-和 kappa-阿片受体激动剂的作用机制起到减少诱发和自发突触传递的作用海马切片。特别是，这些实验将检验由不同的电压依赖性钙通道做出的贡献，细胞内钙储存和一氧化氮支持突触该过程的传输和调制。第二组实验将直接确定阿片类激动剂对含有γ-氨基丁酸（GABA）的神经元亚群（中间神经元）位于海马 CA1 区，细胞这些受体利用影响这些细胞的机制。这些通过使用微分干涉将有助于实验对比显微镜来识别活体脑切片中的这些神经元。这第三组实验将确定是什么机制解释了某些非阿片肽减弱行为和行为的能力阿片类药物的细胞作用。因此，我们将确定以下效果：胆囊收缩素 (CCK) 肽和神经肽 FF 在神经元中发现海马体和导水管周围灰质。调查描述在这个赠款提案中应该提高我们对具体项目的理解阿片类药物作用的受体亚型、细胞机制调节他们的反应，阿片类药物可能发挥神经调节剂的作用在大脑中，以及它们与其他非阿片类药物相互作用的机制肽。此外，由于像海马体这样的边缘结构具有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，以及导水管周围灰质已被证明在介导阿片类镇痛方面很重要，这些研究可能会对阿片类药物和阿片类药物之间的相互作用产生新的见解这些现象。