Understanding how the widely-abused opiate drugs influence brain function requires a better understanding of how the endogenous opioid peptides normally act as neurotransmitters and how their function is altered by chronic opiate abuse. Substantial progress has been made in defining the molecular forms, tissue distribution, specific receptors, and pharmacological actions of the endogenous opioid peptides, yet little is known about their normal physiological role in the mammalian nervous system. We need to know what controls opioid peptide release, where endogenous opioids act, and what physiological effects they normally have. During the past several years, we have been using the rodent hippocampal slice preparation as a model to study the actions of endogenous opioid peptides. In this study, we will define the effects of endogenously released opioid peptides (the dynorphins and enkephalins) on the electrophysiological properties of identified hippocampal neurons. The studies described will examine anatomical structure and physiological properties of the opioid peptide synapses present in the hippocampus. We will determine the distribution of the opioid peptides and opioid receptors using specific antisera, and we will identify the electrophysiological actions of endogenous opioid peptides at three different sites in the hippocampus. We propose to characterize the transmitter properties of 1) the endogenous dynorphins present in the granule cells which regulate excitatory transmission in the dentate gyrus, 2) the endogenous enkephalins present in perforant path axons which regulate inhibitory transmission in the dentate gyrus, 3) the endogenous dynorphins present in the mossy fiber axons which regulate excitatory transmission in the CA3 region of the hippocampus. The effects of chronic morphine and kappa agonist exposure on the functioning of the endogenous opioid system will also be determined. Information obtained from this study will allow us to construct a detailed description of the role of endogenous opioid peptides in the hippocampal neural network and provide a model of opioid neuropeptide action in normal and opiate tolerant hippocampal physiology.
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