BLOCKADE OF TOLERANCE TO MORPHINE BUT NOT TO KAPPA-OPIOIDS BY A NITRIC-OXIDE SYNTHASE INHIBITOR

The nitric oxide synthase inhibitor N(G)-nitro-L-arginine (NO2Arg) blo cks morphine tolerance in mice. After implantation of morphine pellets the analgesic response decreases from 100% on the first day to 0% on the third. Coadministration of NO2Arg along with the pellets markedly retards the development of tolerance; 60% of mice are analgesic after 3 days, and 50% of mice are analgesic after 5 days. In a daily injecti on paradigm the analgesic response to morphine is reduced from 60% to 0% by 5 days. Concomitant administration of morphine along with NO2Arg at doses of 2 mg/kg per day prevents tolerance for 4 weeks. A single NO2Arg dose retards morphine tolerance for several days, and dosing ev ery 4 days is almost as effective as daily NO2Arg. NO2Arg slowly rever ses preexisting tolerance over 5 days despite the continued administra tion of morphine along with NO2Arg. NO2Arg also reduces dependence and reverses previously established dependence. NO2Arg does not prevent t olerance to analgesia mediated by the kappa1 agonist -[2-(1-pyrrolindi nyl)cyclohexyl]-benzene-acetamide (U50,488H) or the kappa3 agent nalox one benzoylhydrazone, indicating a selective action of NO in the mecha nisms of mu tolerance and dependence.