FURTHER EVIDENCE THAT NITRIC-OXIDE MODIFIES ACUTE AND CHRONIC MORPHINE ACTIONS IN MICE

The effects of the nitric oxide (NO) synthase inhibitor, NW-nitro-L-ar ginine (L-NNA, 2.5-10 mu g i.c.v.), and the NO synthesis precursor, L- arginine (L-Arg, 2.5-10 mu g i.c.v.), on morphine-induced analgesia, a nd on morphine-induced tolerance and dependence were examined in mice. Administration of L-NNA diminished the morphine-induced analgesia. L- Arg pretreatment increased the analgesic effect of morphine. Repeated pretreatment (three times, at 24-h intervals) with L-NNA diminished bo th acute and chronic tolerance to morphine, whereas both the acute and the chronic morphine-induced tolerance increased after the repeated ( three times, at 24-h intervals) administration of L-Arg. Neither L-NNA nor L-Arg affected the signs of morphine dependence, as assessed by n aloxone (1 mg/kg, s.c.)-precipitated withdrawal. Our data suggest that increased NO synthesis potentiates morphine analgesia and enhances th e development of morphine tolerance in mice. (C) 1998 Elsevier Science B.V. All rights reserved.