Role of β-endorphin, corticotropin-releasing hormone, and autonomic nervous system in mediation of the effect of chronic ethanol on natural killer cell cytolytic activity

Background: We have recently shown that alcohol feeding suppresses natural killer (NK) cell cytolytic activity partly by decreasing the function of hypothalamic beta-endorphin (beta-EP) neurons. The neuronal mechanism by which hypothalamic beta-EP communicates with the spleen to regulate the action of ethanol on NK cells is not known. In the present study, we evaluated the roles of beta-EP neurons, corticotropin releasing hormone (CRH) neurons, and the autonomic nervous system (ANS) in regulation of the ethanol effect on splenic NK cell cytolytic function. Methods: Male rats were fed an ethanol-containing liquid diet or control diets. These rats were used to determine the hormone release from the paraventricular nuclei (PVN) of the hypothalamus or used to determine the splenic NK cell cytolytic function after PVN administration of CRH or intraperitoneal (i.p.) administration of a ganglionic blocker chlorisondamine. The release of hormones from the PVN was measured using the push-pull perfusion method. Splenic cytolytic activity was determined using the 4-hour Cr-51 release assay against YAC-1 lymphoma target cells. Results: Alcohol feeding decreased the amount of beta-EP but increased the amount of CRH in the push-pull perfusate (PPP) samples collected from the PVN. When exogenous beta-EP was perfused into the PVN, it suppressed the release of endogenous CRH found in PPP samples of the PVN. Conversely, perfusion of an opiate antagonist naltrexone into the PVN increased the levels of endogenous CRH in PPP samples of the PVN. In addition, administration of exogenous beta-EP in the PVN stimulated the cytolytic function of NK cells, an action that was antagonized by CRH as well as by ethanol. Corticotropin-releasing hormone and ethanol alone also had an inhibitory action on NK cells. Finally, the ganglionic blocker used prevented the effect that ethanol, beta-EP, and CRH had on NK cells. These data suggest that ethanol inhibits the function of NK cells partly by suppressing the influence of the beta-EP-CRH-ANS signal to the spleen.