The possible role of PGs and NO in the development of S of DBA/2J mice was investigated by evaluating the effects of dexamethasone, indometacin, mifepristone plus dexamethasone on the S, as well as of L-NAME both on the S in the electrocorticogram of DBA/2J mice and on morphine- and deltorphin II-induced EEG seizure in rabbits. The results of our data indicate that: a) Both dexamethasone and indometacin (1,10,100 μg/kg/i.p.) reduced the S of DBA/2J mice and mifepristone, a glucocorticoid receptor antagonist (1,10,100 μg/kg/i.p.), totally blocked the steroid effect b) L-NAME (3 – 300 μg/mouse/ i.c.v.) dose-dependently reduced the S of DBA/2J mice whereas DNAME at the same doses did not affect S of mice. The inhibitory effect of L-NAME on S of mice was dose-dependently reversed by L-arginine (L-ARG, 3 – 300 μg/mouse/ i.c.v.) but not by D-arginine. Finally, GTN its own (3 – 300 μg/mouse/ i.c.v.) significantly increased the S of mice and it was also able to reverse the inhibition on S of mice operated by L-NAME. c) Morphine and deltorphin II (100 μg/icv/toto) produce EEG seizure activity in rabbits and L-NAME (300 μg/i.c.v./toto), injected 15 min before morphine or deltorphin II, dose dependently prevented the EEG ictal episodes, the spiking activity and the synchronized EEG pattern induced by morphine or deltorphin II. The inhibitory effect of L-NAME on morphine or deltorphin II seizures was dose-dependently reversed by L-arginine (300 μg/icv/toto) but not by D-arginine. Finally, GTN on its own (300 μg/icv/toto) significantly increased morphine or deltorphin II seizures in the rabbit and it was also able to reverse the inhibition on morphine or deltorphin II seizures operated by L-NAME. These results provide a strong evidence that both PGs and NO may play a significant role in the development of brain excitability.