The role of the interaction between endogenous opioids and nitric oxide inthe pathophysiology of ethanol-induced gastric damage in cholestatic rats

Interaction between endogenous opioids and nitric oxide (NO) has been shown in different biological models and pharmacological evidence suggest that o pioids can induce NO release in endothelium as well as in neural cells. Cho lestasis is associated with NO overproduction. The reason for increased NO synthesis is not clearly known but it can potentiate development of gastric mucosal damage in cholestatic subjects. Based on increased plasma levels o f endogenous opioids and existence of NO overproduction in cholestasis, the present experiments were performed to investigate the role of interaction between endogenous opioids and NO in generation of ethanol-induced gastric damage in cholestatic rats. Cholestasis was induced by surgical ligation of bile duct and sham-operated rats served as controls. The animals received either 20 mg/kg of naltrexone or saline for 6 days and then were fasted and received L-arginine (200 mg/kg), N-G-nitro-L-arginine methylester (L-NAME; 2, 5 and 10 mg/kg) or saline. The ethanol-induced gastric mucosal damage w as significantly more severe in cholestatic rats than in sham-operated anim als (115 +/- 12 mm(2) vs. 72 +/- 11 mm(2), P < 0.05). L-NAME significantly enhanced the development of gastric mucosal lesions in sham-operated rats. But in cholestatic animals, L-NAME decreased and L-arginine enhanced the se verity of gastric damage. Pretreatment of animals with naltrexone decreased severity of gastric mucosal damage in cholestatic rats. Concurrent adminis tration of naltrexone with L-arginine was protective against ethanol-induce d gastric damage in both normal and cholestatic groups. Administration of n altrexone with L-NAME had the same effect in cholestatic and control rats a nd increased severity of gastric damage. Plasma levels of NO2- + NO3- were significantly higher in cholestatic rats than control animals (72 +/- 6 muM vs. 39 +/- 3 muM, P < 0.05). Pretreatment of animals with naltrexone signi ficantly reduced plasma levels of NO2- + NO3- in cholestatic animals, but n ot in control rats (33 +/- 6 muM vs. 32 +/- 4 muM). The protective effect o f L-NAME against gastric damage in cholestatic rats can be explained by inh ibition of NO overproduction and it seems that interaction between opioids and NO may have an important role in generation of NO overproduction and ga stric complications in cholestatic rats.