Attenuation of tolerance to, and physical dependence on, morphine in the rat by inhibition of nitric oxide synthase.

1. The effect of NG-monomethyl-L-arginine (NMMA), an inhibitor of nitric oxide synthase (NOS), on the development of tolerance to and physical dependence on morphine was determined in the rat. 2. Male Sprague-Dawley rats were rendered tolerant to and dependent on morphine by the subcutaneous implantation of four morphine pellets (each containing 75 mg morphine base) during a 3 day period. Placebo pellet implanted rats served as controls. 3. Chronic administration of morphine resulted in the development of tolerance to the analgesic action of morphine. Twice daily injections of NMMA (4 or 8 mg/kg) attenuated the tolerance to morphine as evidenced by higher analgesic response in NMMA treated than in vehicle treated morphine tolerant rats. 4. Chronic administration of morphine also resulted in the development of physical dependence as evidenced by the appearance of a variety of symptoms including stereotyped jumping response following naltrexone injection. Concurrent treatment with NMMA inhibited naltrexone-induced jumping response but other responses like fecal boli formation, wet dog shakes, teeth chattering, rearing and ejaculations were not modified. 5. It is concluded that inhibition of NOS can attenuate the development of tolerance to, and physical dependence on, morphine in the rat. However, it appears that higher doses of NOS inhibitors are required in the rat than in the mouse for blockade of both tolerance and physical dependence processes.