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.
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