The biochemical correlates of opiate tolerance and dependence will be studied in the neuroblastoma x glioma (NG108-15) model system, which undergoes changes in the opioid receptors and in the adenylate cyclase complex that mimic opiate tolerance and dependence. Accordingly, the project will be divided in two studies. 1. Study on Dependence. The biochemical changes induced by opiates in the adenylate cyclase stimulatory pathway will be characterized. This pathway involves the GTP-binding regulatory protein, Ns (G/F or Gs), and several regulatory factors. It will be determined whether there is any change in the amount, distribution or any covalent modification of Ns, or any change in the regulatory factors. These studies will help to characterize the mechanism of the compensatory hyperactivity of the adenylate cyclase complex produced by opiates. To characterize the nature of the opiate withdrawal, the proteins phosphorylated by the naloxone-induced cAMP rebound response in the NG108-15 cells will be identified and purified. Phosphorylation of ionic channels or regulatory proteins might explain the neuronal excitability that characterizes the withdrawal syndrome. 2. Study on Tolerance. It will be determined whether there is any quantitative or qualitative change in the GTP binding inhibitory protein produced by prolonged opiate treatment.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA002013-07
Application #
3207077
Study Section
(DABB)
Project Start
1978-06-01
Project End
1989-06-30
Budget Start
1987-07-01
Budget End
1988-06-30
Support Year
7
Fiscal Year
1987
Total Cost
Indirect Cost
Name
New York University
Department
Type
Schools of Medicine
DUNS #
004514360
City
New York
State
NY
Country
United States
Zip Code
10012
Zhou, G Z; Musacchio, J M (1991) Computer-assisted modeling of multiple dextromethorphan and sigma binding sites in guinea pig brain. Eur J Pharmacol 206:261-9
Klein, M; Canoll, P D; Musacchio, J M (1991) SKF 525-A and cytochrome P-450 ligands inhibit with high affinity the binding of [3H]dextromethorphan and sigma ligands to guinea pig brain. Life Sci 48:543-50
Canoll, P D; Smith, P R; Gottesman, S et al. (1990) Autoradiographic localization of [3H]dextromethorphan (DM) in guinea pig brain: allosteric enhancement by ropizine. Prog Clin Biol Res 328:171-4
Klein, M; Musacchio, J M (1990) Computer-assisted analysis of dextromethorphan and (+)-3-(-3-hydroxyphenyl)-N-(1-propyl)piperidine binding sites in rat brain. Allosteric effects of ropizine. Life Sci 47:1625-34
Musacchio, J M; Klein, M; Canoll, P D (1990) Dextromethorphan sites, sigma receptors, and the psychotomimetic effects of sigma opiates. Prog Clin Biol Res 328:13-6
Klein, M; Zhou, G Z; Paturzo, J J et al. (1990) The effect of sigma ligands on dextromethorphan binding sites in the guinea pig. Prog Clin Biol Res 328:129-32
Canoll, P D; Smith, P R; Musacchio, J M (1990) Ropizine concurrently enhances and inhibits [3H]dextromethorphan binding to different structures of the guinea pig brain: autoradiographic evidence for multiple binding sites. Life Sci 46:PL9-16
Canoll, P D; Smith, P R; Gottesman, S et al. (1989) Autoradiographic localization of [3H]dextromethorphan in guinea pig brain: allosteric enhancement by ropizine. J Neurosci Res 24:311-28
Klein, M; Musacchio, J M (1989) High affinity dextromethorphan binding sites in guinea pig brain. Effect of sigma ligands and other agents. J Pharmacol Exp Ther 251:207-15
Klein, M; Paturzo, J J; Musacchio, J M (1989) The effect of prototypic sigma ligands on the binding of [3H]dextromethorphan to guinea pig brain. Neurosci Lett 97:175-80

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