MORPHINE AFFECTS CYTOSTATIC ACTIVITY OF MACROPHAGES BY THE MODULATIONOF NITRIC-OXIDE RELEASE

The serum levels of morphine and its glucuronide metabolites were quan titated in C57BL/6 mice at various intervals following subcutaneous ad ministration of morphine. Since one of the major mechanisms of killing by macrophages is the production of nitric oxide, pharmacokinetics da ta were correlated with cytostatic activity and the release of NO2- (s table end product of NO metabolism). Morphine and its 3-glucuronide me tabolite appear in serum of treated mice, reaching a peak of concentra tion at 20 min However, morphine 3'-glucuronide levels were much highe r than those of the drug itself, even when the morphine concentration levelled off. Both cytostasis and NO2- production of L1210-activated m acrophages were significantly enhanced by opioid treatment immediately after drug injection (peaking after 40 min). In contrast, morphine in duced a strong inhibition of both cytostasis and NO2- production 24 h after treatment. The modulation of both cytostasis and NO2- production induced by morphine was completely antagonized by pretreatment of mic e with the opioid antagonist naltrexone. The involvement of an inducib le isoform of NO synthase was suggested by the inhibitory effects of d examethasone on NO2- production. These data indicate that in vivo admi nistration of morphine can induce a modulation of the NO biosynthesis of peritoneal macrophages.