EVIDENCE FOR A ROLE OF NITRIC-OXIDE OF THE CENTRAL-NERVOUS-SYSTEM IN MORPHINE ABSTINENCE SYNDROME

Two patent inhibitors of nitric oxide synthase (NOS), namely, N-G-nitr o-L-arginine (NNA) and N-G-monomethyl-L-arginine (NMMA) were administe red intracerebroventricularly (i.c.v.) in morphine-dependent mice to i nvestigate their effects on abrupt withdrawal and naltrexone-precipita ted abstinence signs. Male Swiss-Webster mice were rendered dependent on morphine by subcutaneous implantation of a morphine pellet containi ng 75 mg of morphine base. Mice implanted with placebo pellets served as controls, NMMA or NNA administered i.c.v. had minimal effects on bo dy weight loss and hypothermia that occur during abrupt withdrawal of morphine, When administered i.c.v., both NNA or NMMA (0.1, 1 and 10 mu g/mouse) dose-dependently inhibited naltrexone-induced stereotyped ju mping behavior in mice. I.c.v. administration of NMMA also attenuated withdrawal induced fecal pellet formation. This effect, however, was n ot dose-dependent, In conclusion, these results suggest that brain NO plays an important role in the expression of behavioral signs of morph ine withdrawal syndrome. In addition, these results support the idea t hat NOS inhibitors may be potentially useful in the treatment of opioi d withdrawal syndrome.