PHYSIOLOGY AND PHARMACOLOGY OF OPIOIDS IN BRAIN

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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.