The long-range goal of these studies is to understand the mechanisms by which opiates and opioid peptides alter normal neuronal function by analyzing receptor-mediated events in cultured cells of nervous system origin. We propose to use neurotumor cells and sensory neurons that possess Mu, Kappa and Delta receptors to study both the acute and chronic effects of opiates and opioid peptides so that eventually we can devise a rational therapy for narcotic addiction. Acute effects of opiates (0-30min) will be studied in a neuroblastoma x Chinese hamster neuron hybrid cell line (NCB-20) which expresses both delta (enkephalin) and sigma-like (benzomorphan) opiate receptors and voltage-sensitive calcium channels (VSCC), and in rat pheochromocytoma (PC12) cells which express VSCC, release neurotransmitters such as norepinephrine (NE), and which can be induced with NGF to express enkephalin receptors. Particular emphasis will be placed on the role of opiates in regulating calcium fluxes internal calcium mobilization, cyclic AMP-dependent protein phosphorylation, calcium-dependent protein phosphorylation, polyphosphoinositide turnover, inositol triphosphate release and modulation of K+ flux. We will also use dorsal root ganglion cells in which substance P release, evoked by cell depolarization, is blocked by opiate agonists. It is our primary hypothesis that an opiate-induced reduction of cellular cyclic AMP levels may result in a reduced phosphorylation of a dihydropyridine-sensitive calcium channel in these cells. This would lead to a reduction in evoked influx of calcium ions and subsequent inhibition of transmitter release.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA002575-10
Application #
3207422
Study Section
(DABB)
Project Start
1980-04-01
Project End
1990-05-31
Budget Start
1989-04-01
Budget End
1990-05-31
Support Year
10
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of Chicago
Department
Type
Schools of Medicine
DUNS #
225410919
City
Chicago
State
IL
Country
United States
Zip Code
60637
Sun, L; Miller, R J (1999) Multiple neuropeptide Y receptors regulate K+ and Ca2+ channels in acutely isolated neurons from the rat arcuate nucleus. J Neurophysiol 81:1391-403
Fatatis, A; Miller, R J (1999) Cell cycle control of PDGF-induced Ca(2+) signaling through modulation of sphingolipid metabolism. FASEB J 13:1291-301
Ford, C E; Skiba, N P; Bae, H et al. (1998) Molecular basis for interactions of G protein betagamma subunits with effectors. Science 280:1271-4
Jordan, J; Galindo, M F; Miller, R J et al. (1998) Isoform-specific effect of apolipoprotein E on cell survival and beta-amyloid-induced toxicity in rat hippocampal pyramidal neuronal cultures. J Neurosci 18:195-204
Simen, A A; Miller, R J (1998) Structural features determining differential receptor regulation of neuronal Ca channels. J Neurosci 18:3689-98
Lee, C C; Miller, R J (1998) Is there really an NPY Y3 receptor? Regul Pept 75-76:71-8
Bindokas, V P; Lee, C C; Colmers, W F et al. (1998) Changes in mitochondrial function resulting from synaptic activity in the rat hippocampal slice. J Neurosci 18:4570-87
Kinney, G A; Emmerson, P J; Miller, R J (1998) Galanin receptor-mediated inhibition of glutamate release in the arcuate nucleus of the hypothalamus. J Neurosci 18:3489-500
Sun, L; Philipson, L H; Miller, R J (1998) Regulation of K+ and Ca++ channels by a family of neuropeptide Y receptors. J Pharmacol Exp Ther 284:625-32
Jordan, J; Galindo, M F; Prehn, J H et al. (1997) p53 expression induces apoptosis in hippocampal pyramidal neuron cultures. J Neurosci 17:1397-405

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