Model System Studies of Naltrexone and Alcohol Interaction

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DESCRIPTION (provided by applicant): Naltrexone is used for the treatment of drug addiction including alcoholism. A potential use of naltrexone in controlling the immune-suppressive effect of alcohol has recently been identified. In particular, naltrexone enhances the effects of opioid ligands on natural killer cell functions. The underlying molecular basis for these observations is not known. We propose that the modulation of receptor function by physical association between mu and delta opioid receptors is a potential mechanism. We also hypothesize that the occupancy of mu opioid receptors by naltrexone is sufficient to increase the ability of a ligand to bind and induce signaling of delta opioid receptors in natural killer cells. To test these hypotheses, we propose to examine the physical association of mu opioid receptors and delta opioid receptors in natural killer cells by identifying the immune complex of opioid receptors in the membrane of the natural killer cells expressing both opioid receptors or expressing mutated mu receptors using immunoprecipitation techniques. We propose to determine the physiological consequences of opioid receptor oligomerization by evaluating the effects of repression of mu opioid receptors on the levels of delta opioid receptor binding, the signaling by delta-opioid receptors, and the production of cytotoxic factors and cytokines in natural killer cells using various molecular and biochemical techniques. We plan to evaluate whether ethanol inhibition of the NK cell response to endogenous opioid ligands involves alteration of opioid receptor oligomerization by determining the ethanol-induced changes in the levels of opioid receptors immunocomplex, ligand binding, signaling and production of cytotoxic factors and cytokines in natural killer cells. The ability of naltrexone to prevent ethanol-induced alteration of opioid receptor functional coupling will also be evaluated by measuring the changes in the physical association and pharmacology of opioid receptors and the opioid ligands responses of NK cells. The information generated from this study should help us to develop an innovative strategy for combining opioid agonists and antagonists by heterodimeric association to treat immune incompetence in alcoholic and other immune-deficient patients.