This research plan is designed to examine the role of the endogenous dynorphin peptides under a number of normal and pathological conditions. The dynorphins are a family of inhibitory neuropeptides expressed at high concentration within the hippocampal formation. The investigators are guided by two key observations: first, that the dynorphin opioids can be released from granule cells to inhibit excitatory amino acid release both from presynaptic afferents of the perforant path (retrograde inhibition) and from granule cells (autoinhibition). Second, that in both human and animal models of temporal lobe epilepsy, there is often an expansion of the dynorphin-containing fibers in the dentate gyrus as a consequence of synaptic reorganization. These observations lead to the following two hypotheses: that the dynorphin opioids may be neuroprotective by reducing glutamate release during periods of hyperactivity, and that dynorphin-mediated inhibition may serve an expanded role under conditions in which the GABAergic tone is reduced. Pilocarpine-treatment provides an animal model of temporal lobe epilepsy that duplicates many features of human pathology including a loss of a group of hilar GABAergic neurons and an expansion of the dynorphin-containing mossy fibers in the dentate gyrus. The investigators plan to use this model to address the following specific aims: 1) To use anti-opioid receptor antibodies, which can act as specific markers for a subpopulation of GABAergic neurons and excitatory afferents in this region, to identify anatomical changes within the rat dentate gyrus after pilocarpine-induced neurotoxicity. 2) To determine if the anatomical changes in opioid receptor expression correlate with changes in the pharmacological response to opioid agonists on granule cell excitability. 3) To determine whether infusion of kappa opioid receptor selective agonists or antagonists during the pilocarpine-induction of temporal lobe epilepsy will protect or exacerbate the neurodegeneration assessed by anti-receptor antibody labeling. 4) To measure the amplitude and kinetics of the actions of endogenously released dynorphins which regulate excitatory neurotransmission in the dentate gyrus. These approaches will provide a new characterization of the anatomical and physiological changes in neuronal circuitry underlying this animal model of temporal lobe epilepsy. The ultimate goal of these studies is to develop novel strategies for the control or amelioration of this seriously debilitating seizure disorder.
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