Augmenting effect of opioids on nitrite production by stimulated murine macrophages.
The effects of methionine-enkephalin and the selective agonists of mu-, delta- and kappa-opioid receptor subtypes [D-Ala2,N-Me-Phe4,Gly5-ol]enkephalin, [D-Pen(2,5)]enkephalin U-50488 on the production of nitrite by activated peritoneal murine macrophages were studied. Macrophages were activated with interferon-gamma plus lipopolysaccharide in the presence or absence of graded concentrations of opioids. Methionine-enkephalin and mu-; delta- and kappa-agonists combined with interferon-gamma plus lipopolysaccharide caused an increase in nitrite release from cultured macrophages. Only 10 mM U-50488 led to a decrease in nitrite release from interferon-gamma and LPS-stimulated macrophages. This effect was not produced in a naloxone-sensitive manner. The opioids added to the fresh culture 8 h after the stimulation of macrophages by interferon-gamma plus lipopolysaccharide--when an inducible form of nitric oxide synthase activity is presumably expressed--did not alter the rate of nitrite production. This suggests that the effect of opioids on nitric oxide synthase is produced at the transcriptional level. The opioid receptor antagonist naloxone reduced the stimulatory effect of opioids on nitrite production by stimulated macrophages. Opioids added to the culture of resting macrophages did not change nitrite release from macrophages which were later induced with interferon-gamma plus lipopolysaccharide. The results of this study suggest that methionine-enkephalin can modulate the immune response by controlling, via opioid receptors, the production of nitric oxide.
Kowalski
J
J
Department of Clinical Pharmacology, Silesian University School of Medicine, Katowice, Poland.
D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D020881:Enkephalin, D-Penicillamine (2,5)-; D004744:Enkephalin, Methionine / Q000494:pharmacology; D004745:Enkephalins / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009573:Nitrites / Q000378:metabolism*; D018847:Opioid Peptides / Q000494:pharmacology*; D017465:Receptors, Opioid, delta / Q000819:agonists / Q000502:physiology; D017473:Receptors, Opioid, kappa / Q000819:agonists / Q000502:physiology; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000502:physiology
D004745:Enkephalins; D008070:Lipopolysaccharides; D009573:Nitrites; D018847:Opioid Peptides; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D004744:Enkephalin, Methionine; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D007371:Interferon-gamma; D020881:Enkephalin, D-Penicillamine (2,5)-