Nitric oxide mediates the beneficial effect of chronic naltrexone on cholestasis-induced memory impairment in male rats.

Recent studies suggest an augmentation of endogenous opioids following bile duct ligation (BDL) and their pivotal role in the pathophysiology of cholestasis. In this study, the effect of naltrexone, an opioid receptor antagonist, was determined on cholestasis-induced memory impairment and the possible involvement of nitric oxide (NO) in this effect. Male Albino-Wistar rats were randomized to sham-operated and BDL-operated groups. In each group, animals were treated for up to 28 days with saline; naltrexone (10 mg/kg); naltrexone and N(G)-nitro-L-arginine methyl ester (L-NAME), a nonselective nitric oxide synthase (NOS) inhibitor (3, 10 mg/kg); naltrexone and aminoguanidine, an inducible NOS inhibitor (100 mg/kg); or methylnaltrexone, a peripherally acting opioid receptor antagonist (3 mg/kg, intraperitoneal). Spatial recognition memory was determined in a Y-maze task on the day before surgery and days 7, 14, 21, and 28 after surgery. Memory performance was impaired 14 days after BDL in cholestatic rats and was significantly reversed by chronic treatment with naltrexone at days 14, 21, and 28 after BDL. On day 21 after BDL, chronic L-NAME produced only a nonsignificant decrease in the beneficial effect of naltrexone, whereas on day 28, chronic administration of both L-NAME and aminoguanidine significantly reversed this effect of naltrexone. It is therefore shown in this study that naltrexone improves BDL-induced memory deficit in rats. We conclude that the memory impairment in cholestatic rats might be because of an increase in the level of endogenous opioids and that naltrexone improved the spatial recognition memory by antagonizing opioid receptors. The observation that the procognitive effect of naltrexone is counteracted either by general inhibition of NOS enzymes or by selective inhibition of inducible NOS suggests the nitrergic pathway as a probable mechanism involved in the amelioration of spatial recognition memory by naltrexone in BDL rats.