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Morphine affects cytostatic activity of macrophages by the modulation of nitric oxide release
R Pacifici1, M Minetti, P Zuccaro
1Clinical Biochemistry Department, Istituto Superiore di Sanità, Rome, Italy.
Abstract:
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.
Insights
Morphine administration alters macrophage function, impacting nitric oxide (NO) production and cell killing. Opioid effects on NO biosynthesis in macrophages depend on the time after morphine treatment.
Area of Science:
- Pharmacology
- Immunology
- Toxicology
Background:
- Macrophages play a crucial role in host defense, partly through nitric oxide (NO) production.
- Opioid drugs, like morphine, can modulate immune cell functions.
- Understanding morphine's impact on macrophage NO production is vital for assessing its immunomodulatory effects.
Purpose of the Study:
- To investigate the pharmacokinetic profile of morphine and its metabolites.
- To correlate morphine pharmacokinetics with its effects on macrophage cytostatic activity and nitric oxide (NO) production.
- To elucidate the temporal dynamics of morphine's immunomodulatory actions on macrophages.
Main Methods:
- Quantification of serum morphine and glucuronide metabolite levels in C57BL/6 mice post-subcutaneous morphine administration.
- Assessment of macrophage (L1210) cytostatic activity and NO2- (stable NO metabolite) release.
- Correlation of pharmacokinetic data with immunological parameters.
- Evaluation of the effects of opioid antagonist naltrexone and dexamethasone.
Main Results:
- Morphine and its 3-glucuronide metabolite were detected in serum, with glucuronide levels exceeding morphine.
- Macrophage cytostasis and NO2- production were enhanced shortly after morphine treatment but inhibited 24 hours later.
- Naltrexone completely reversed morphine's effects, suggesting opioid receptor involvement.
- Dexamethasone inhibited NO2- production, indicating the involvement of inducible NO synthase.
Conclusions:
- In vivo morphine administration significantly modulates peritoneal macrophage nitric oxide biosynthesis.
- The immunomodulatory effects of morphine on macrophages are time-dependent and mediated via opioid receptors.
- Morphine's impact on macrophage function involves the regulation of nitric oxide production.