Morphine affects cytostatic activity of macrophages by the modulation of nitric oxide release.
The serum levels of morphine and its glucuronide metabolites were quantitated in C57BL/6 mice at various intervals following subcutaneous administration of morphine. Since one of the major mechanisms of killing by macrophages is the production of nitric oxide, pharmacokinetics data were correlated with cytostatic activity and the release of NO2- (stable end product of NO metabolism). Morphine and its 3-glucuronide metabolite appear in serum of treated mice, reaching a peak of concentration at 20 min. However, morphine 3'-glucuronide levels were much higher than those of the drug itself, even when the morphine concentration levelled off. Both cytostasis and NO2- production of L1210-activated macrophages were significantly enhanced by opioid treatment immediately after drug injection (peaking after 40 min). In contrast, morphine induced 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 mice with the opioid antagonist naltrexone. The involvement of an inducible isoform of NO synthase was suggested by the inhibitory effects of dexamethasone on NO2- production. These data indicate that in vivo administration of morphine can induce a modulation of the NO biosynthesis of peritoneal macrophages.
Pacifici
R
R
Clinical Biochemistry Department, Istituto Superiore di Sanità, Rome, Italy.
Minetti
M
M
Zuccaro
P
P
Pietraforte
D
D
D000701:Analgesics, Opioid / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D003907:Dexamethasone / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009020:Morphine / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D009271:Naltrexone / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D013997:Time Factors
D000701:Analgesics, Opioid; D009569:Nitric Oxide; D009271:Naltrexone; D009020:Morphine; D003907:Dexamethasone