Understanding how the widely-abused opiate drugs influence brain function requires a better understanding of how the endogenous opioid peptides normally act as neurotransmitters. During the previous cycle of this project, we established the novel finding that opioid receptor activation causes presynaptic inhibition by an increase in a delayed rectifying potassium conductance in the nerve terminal, an observation that has been recently confirmed. Opioid-induced presynaptic inhibition of neurotransmitter release is likely to be an important mode of endogenous opioid action in many regions of the brain and peripheral nervous system. Thus, the mechanism of this opioid effect and the biophysical characteristics of the potassium channel activated will be important to define. The proposal has four components: First, we propose to characterize the signal transduction events linking the opioid receptor to potassium channel in the nerve terminals synapsing on hippocampal pyramidal and dentate granule cells by using specific pharmacological antagonists and agonists. Next, we propose to identify the specific potassium channel activated in these nerve terminals by using channel-specific toxins and mouse strains having gene deletions (""""""""knock-outs"""""""") of candidate channels. Third, we propose to continue our electrophysiological studies of opioid-activated delayed rectifying potassium channels expressed in the somata of hippocampal interneurons to define the potential mechanisms linking opioid receptors to voltage-gated K channels in these more accessible regions of the opioid-responsive neuron. Finally, we propose to reconstitute the signal transduction events in a malleable model system by expressing opioid receptors, candidate potassium channels, and proposed intermediate effectors in Xenopus oocytes. Information obtained from this study will allow us to understand the events underlying an important type of opioid-induced, presynaptic inhibition of transmitter release.
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