The additive effect of opioids and nitric oxide in increasing pentylenetetrazole-induced seizure threshold in cholestatic mice

BACKGROUND: Accumulation of endogenous opioids and overproduction of nitric oxide has been reported in cholestatic mice. It is well known that endogenous opioids and nitric oxide alter the susceptibility of experimental animals to different models of seizure. METHODS: The alterations in clonic seizure thresholds, induced by pentylenetetrazole from 1 to 6 days after bile duct ligation, were evaluated in mice. Whether the pretreatment of cholestatic mice with different doses of opioid receptor antagonist naltrexone, or nitric oxide inhibitor N(omega)-nitro-L-arginine methyl ester would have changed the clonic seizure threshold was also examined. RESULTS: While in sham-operated mice the clonic seizure threshold was similar to that of the thresholds in unoperated controls, a time-dependent increase in the threshold was observed in cholestatic mice, reaching a peak on day 3 after bile duct ligation and declining partially after the 4th day. Chronic pretreatment with naltrexone (2, 5 and 10 mg/kg, i.p.) reversed the increased threshold in cholestatic mice on day 3 after operation in a dose-dependent manner with the highest doses used restoring the threshold to that of the control animals. A similar reversal of the increased threshold was observed after acute (1, 3 and 10 mg/kg, i.p.) or chronic (10 mg/kg, i.p. for 4 days) pretreatment with N(omega)-nitro-L-arginine methyl ester. Moreover, concurrent administration of doses of N(omega)-nitro-L-arginine methyl ester and naltrexone that each separately induced a partial reversal of increased seizure threshold in cholestasis caused a complete restoring of the threshold to the control level. CONCLUSIONS: Based on these findings, both opioid receptors and nitric oxide may be involved in the dramatic increase in pentylenetetrazole-induced seizure threshold in cholestasis.