PHYSIOLOGY AND PHARMACOLOGY OF OPIOIDS IN BRAIN

已知阿片类药物具有重要的行为和生理作用 通过与中枢神经系统中的神经元相互作用 系统然而，虽然阿片类药物的行为，包括 镇痛和欣快，是众所周知的，功能作用，这些 在哺乳动物大脑中作为神经调节剂的分子仍然很差， 明白 下面的实验将评估 阿片类，作用于定义的μ-、δ-和κ-阿片类 受体亚型，作为CA 1中突触传递的调节剂， 海马的齿状回区域，而在另一个大脑区域， 被称为中脑导水管周围灰质本文中描述的实验 建议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作用的检测技术 脑切片制备。第一组实验将集中在 μ-、δ-和κ-阿片受体激动剂 作用于减少诱发和自发突触传递， 海马切片特别是，这些实验将检查 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在支持突触 传输和调制这个过程。第二组 实验将确定阿片激动剂直接对 含γ-氨基丁酸（GABA）神经元亚群 （中间神经元）在海马CA 1区，和细胞 这些受体用来影响这些细胞的机制。 这些 实验将通过使用微分干涉来辅助 对比显微镜来识别活体脑切片中的这些神经元。的 第三组实验将确定是什么机制导致了 某些非阿片肽减弱行为和 阿片类药物的细胞作用。因此，我们将确定 胆囊收缩素（CCK）和神经肽FF在神经元上发现， 海马体和导水管周围灰质调查描述了 在这个赠款建议应该提高我们的理解，具体的 阿片类药物作用的受体亚型，细胞机制 阿片类药物可能作为神经调节剂， 以及它们与其他非阿片类药物相互作用的机制 缩氨酸此外，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， 学习，癫痫，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中是重要的，这些 研究可能会产生新的见解，阿片类药物和 这些现象。

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.