Naltrexone, an opioid antagonist, has been used in clinical trials to treat alcoholism. As the opioid peptides beta-endorphin and enkephalin increase splenic NK cell function in laboratory animals, it is anticipated that naltrexone treatment will cause immunosuppression. However, we report in this study that chronic naltrexone administration in laboratory rats increases the cytolytic activity of NK cells. It also prevents alcohol's suppressive effect on these cells. We identified that, in the splenocytes, delta opioid receptor expression is tightly controlled by negative feedback regulation of micro opioid receptors. Naltrexone disrupts this feedback control by reducing micro opioid receptor function, thereby up-regulating delta opioid receptor binding, which results in an enhanced NK cell cytolytic response to delta opioid receptor ligands. We conclude that naltrexone, which has been shown to be a promising agent for the clinical management of alcoholism, may have potential use in the treatment of immune deficiency in alcoholic and nonalcoholic patients.