The role of specific eicosanoids in mediating the acute narcotic effects of ethanol

The pharmacological effects of ethanol may be in part due to increased membrane fluidity, resulting in increased phospholipase A2 activity and the subsequent conversion of released arachidonic acid (AA) into pharmacologically relevant eicosanoids (prostaglandins/leukotrienes). A significant correlation between the in vivo and in vitro potency of prostaglandin synthetase (PES) inhibitors to antagonize PES activity and their ability to antagonize the acute narcotic and rate-depressant effects of ethanol support this hypothesis. However, inhibition of PES not only decreases the production of at least five prostaglandins and thromboxane but may shunt free AA into the lipoxygenase cascade with subsequent formation of leukotrienes. The purpose of the present study was to systematically investigate numerous points in the AA cascade to determine the eicosanoid products relevant to the acute narcotic effects of ethanol. Ethanol-induced loss of the righting reflex in mice was used as the behavioral endpoint. The relative importance of PES metabolites vs. lipoxygenase metabolites was determined via administration of specific enzyme inhibitors (phospholipase, lipoxygenase and dual PES/lipoxygenase inhibitors) and receptor agonists/antagonists (prostaglandin and leukotriene). Pretreatment with specific lipoxygenase inhibitors, dual PES/lipoxygenase inhibitors and leukotriene antagonists suggest a negligible role for lipoxygenase metabolites in acute ethanol-induced narcosis. Pretreatment with prostaglandin agonists and antagonists suggest a significant role for prostaglandin E (PGE) and a minor role for prostaglandin D in mediating the acute effects of ethanol. The PGE agonist 16,16-dimethyl PGE significantly enhanced the narcotic effects of ethanol (> 400%), whereas the prostaglandin receptor antagonist L-640,035 significantly decreased the effects of ethanol (-54%). These results further support the hypothesis that eicosanoid formation is important in the biochemical and behavioral effects of ethanol.