The proposed research will explore the nature of the dynorphins, a class of endogenous opioid peptides, interaction with opioid receptors in a particular brain region of the rat and guinea pig. The goal of these studies is to provide a detailed understanding of the actions of an endogenous neuropeptide at a site of its synthesis and release, and thus ultimately to provide an important model of endogenous opioid action. Our specific hypothesis is that the dynorphin peptides are synthesized by dentate granule cells and released at their mossy fiber terminals to control the excitability of hippocampal pyramidal neurons. Preliminary evidence obtained has supported this idea: We have demonstrated the presence of the dynorphin opioid peptides in the rat hippocampus, the in vitro release of these peptides from hippocampal slices, and the effects of exogenously applied opioids on hippocampal cell excitability. These data strongly suggest that the dynorphin opioids are likely to be neurotransmitters in the rat hippocampus. We plan to test our hypothesis by further delineating the actions of opioids and the properties of the opioid receptors present in this brain region. Electrophysiological recording methods will be used to measure responses to the dynorphins in hippocampal slices; the pharmacological effects of opioids will be quantified; responses to endogenously released opioids will be identified, and the opioid receptor types mediating the effects of both exogenously applied and endogenously released opioids will be defined. To accomplish these goals we will record the effects of the dynorphins applied to likely hippocampal cell targets in the pyramidal and dentate granule cell layers. We propose to 1) define the effects of dynorphin by intracellularly recording cell excitability while applying peptide by micropipette; 2) characterize the specific opioid receptors that mediate the pharmacological effects of the dynorphins at opioid sensitive sites in the hippocampus; 3) identify the effects of endogenously released dynorphins by stimulating the peptide-containing fiber tracts and measuring the opioid antagonist sensitive effects.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS023483-01
Application #
3407021
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Project Start
1986-08-01
Project End
1989-07-31
Budget Start
1986-08-01
Budget End
1987-07-31
Support Year
1
Fiscal Year
1986
Total Cost
Indirect Cost
Name
University of Washington
Department
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
Caudle, R M; Chavkin, C (1990) Mu opioid receptor activation reduces inhibitory postsynaptic potentials in hippocampal CA3 pyramidal cells of rat and guinea pig. J Pharmacol Exp Ther 252:1361-9
Wimpey, T L; Caudle, R M; Chavkin, C (1990) Chronic morphine exposure blocks opioid effects on both the early and late inhibitory postsynaptic potentials in hippocampal CA1 pyramidal cells. Neurosci Lett 110:349-55
Neumaier, J F; Chavkin, C (1989) Calcium-dependent displacement of haloperidol-sensitive sigma receptor binding in rat hippocampal slices following tissue depolarization. Brain Res 500:215-22
Swearengen, E; Chavkin, C (1989) Comparison of opioid and GABA receptor control of excitability and membrane conductance in hippocampal CA1 pyramidal cells in rat. Neuropharmacology 28:689-97
Neumaier, J F; Chavkin, C (1989) Release of endogenous opioid peptides displaces [3H]diprenorphine binding in rat hippocampal slices. Brain Res 493:292-302
Malouf, A T; Swearengen, E; Chavkin, C (1988) Comparison of the actions of phencyclidine and sigma ligands on CA1 hippocampal pyramidal neurons in the rat. Neuropharmacology 27:1161-70
Neumaier, J F; Mailheau, S; Chavkin, C (1988) Opioid receptor-mediated responses in the dentate gyrus and CA1 region of the rat hippocampus. J Pharmacol Exp Ther 244:564-70
Chavkin, C; Neumaier, J F; Swearengen, E (1988) Opioid receptor mechanisms in the rat hippocampus. NIDA Res Monogr 82:94-117
Swearengen, E; Chavkin, C (1987) NMDA receptor antagonist D-APV depresses excitatory activity produced by normorphine in rat hippocampal slices. Neurosci Lett 78:80-4