COMPARATIVE EFFECTS OF N-G-MONOMETHYL-L-ARGININE AND MK-801 ON THE ABSTINENCE SYNDROME IN MORPHINE-DEPENDENT MICE

The effects of N-G-monomethyl-L-arginine (L-NMMA), an inhibitor of nit ric oxide.(NO) synthase and MK-801, an NMDA receptor antagonist on abr upt and naltrexone-precipitated abstinence symptoms were determined in male Swiss-Webster mice rendered dependent on morphine by subcutaneou s implantation of a pellet containing 75 mg of morphine base for 3 day s. Mice which served as controls were implanted with placebo pellets. Six hours after pellet removal, mice were injected intraperitoneally w ith either the vehicle or MK-801 (0.03, 0.1 and 0.3 mg/kg). Thirty min utes later the animals were injected with naltrexone subcutaneously (5 0 mu g/kg) and the intensity of abstinence symptoms were determined. O f the three doses of MK-801 used, only 0.1 mg/kg dose inhibited the ju mping behavior precipitated by naltrexone in morphine-dependent mice. Whereas the lower dose (0.03 mg/kg) of MK-801 increased, the higher do ses of MK-801 (0.1 and 0.3 mg/kg) displayed a decrease in the formatio n of fecal boli. Administration of MK-801 did not affect the body weig ht loss observed during abrupt withdrawal (induced by removal of the p ellets) in morphine-dependent mice. MK-801 at 0.1 mg/kg dose further d ecreased the body temperature during abrupt withdrawal in morphine-dep endent mice. Other two doses of MK-801 (0.03 and 0.3 mg/kg) did not mo dify the hypothermia observed during abrupt morphine withdrawal. On th e other hand, L-NMMA (0.02 to 4.0 mg/kg) injected intraperitoneally 15 min prior to the naltrexone administration blocked the stereotyped ju mping response in a dose-dependent manner. Higher doses of L-NMMA 2.0 and 4.0 mg/kg also decreased the number of fecal boli formation. L-NMM A (0.2 to 4.0 mg/kg) also significantly reduced the abrupt withdrawal- induced body weight loss in morphine-dependent mice. Thus, MK-801 has very little effect, which is not dose-dependent, on abrupt and antagon ist-precipitated withdrawal in morphine-dependent mice. However, the L -NMMA has more profound dose-dependent effects on both the abrupt and antagonist-precipitated withdrawal in morphine-dependent mice. It is c oncluded that the inhibitors of NO synthase may be more beneficial tha n NMDA receptor antagonists in managing the symptoms of morphine absti nence syndrome.