Inhibition of nitric oxide synthase attenuates the development of morphine tolerance and dependence in mice.

The effect of the nitric oxide (NO) synthase inhibitor L-NG-nitroarginine methyl ester (L-NAME, 5-20 mg/kg i.p.) and NG-nitro-L-arginine (NO2Arg, 5-20 mg/kg i.p.) on morphine-induced analgesia, as well as on morphine induced tolerance and dependence was examined in male albino Swiss mice. Neither acute nor repeated (for 5 days) administration of the nitric oxide synthase inhibitor, L-NAME affected the morphine induced analgesia, as measured by hot plate and tail-flick tests. On the other hand, administration of L-NAME or NO2Arg along with morphine prevented the development of tolerance to the analgesic effect of morphine for at least 7 days, whereas the analgesic effect of morphine alone disappeared after 5 days. L-NAME and NO2Arg also attenuated some signs of morphine dependence, as assessed by naloxone (2 mg/kg)-precipitated withdrawal. These results indicate that NO may play a role in the development of morphine tolerance and dependence.