kappa-Opioid agonist modulation of [3H]thymidine incorporation into DNA: evidence for the involvement of pertussis toxin-sensitive G protein-coupled phosphoinositide turnover.
A body of evidence has indicated that mu-opioid agonists can inhibit DNA synthesis in developing brain. We now report that kappa-selective opioid agonists (U69593 and U50488) modulate [3H]thymidine incorporation into DNA in fetal rat brain cell aggregates in a dose- and developmental stage-dependent manner, kappa agonists decreased thymidine incorporation by 35% in cultures grown for 7 days, and this process was reversed by the kappa-selective antagonist, norbinaltorphimine, whereas in 21-day brain cell aggregates a 3.5-fold increase was evident. Cell labeling by [3H]thymidine was also inhibited by the kappa-opioid agonist as shown by autoradiography. In addition, U69593 reduced basal rates of phosphoinositide formation in 7-day cultures and elevated it in 21-day cultures. Control levels were restored by norbinaltorphimine. Pertussis toxin blocked U69593-mediated inhibition of DNA synthesis. The action of kappa agonists on thymidine incorporation in the presence of chelerythrine, a protein kinase C (PKC) inhibitor, or in combination with LiCl, a noncompetitive inhibitor of inositol phosphatase, was attenuated in both 7- and 21-day cultures. These results suggest that kappa agonists may inhibit DNA synthesis via the phosphoinositide system with a pertussis toxin-sensitive G protein as transducer. In mixed glial cell aggregates, U50488 increased thymidine incorporation into DNA 3.1-fold, and this stimulation was reversed by the opioid antagonist naltrexone.
E. A. Doisy Department of Biochemistry and Molecular Biology, St. Louis University School of Medicine, Missouri 63104-1079.
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Barg
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Belcheva
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Rowiński
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Coscia
D000470:Alkaloids; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D001345:Autoradiography; D044482:Benzeneacetamides; D053119:Benzophenanthridines; D001921:Brain / Q000187:drug effects / Q000196:embryology* / Q000378:metabolism; D002712:Chlorides / Q000494:pharmacology; D004247:DNA / Q000096:biosynthesis*; D004723:Endorphins / Q000494:pharmacology*; D019204:GTP-Binding Proteins / Q000502:physiology*; D008094:Lithium / Q000494:pharmacology; D018021:Lithium Chloride; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D037342:Pertussis Toxin; D010617:Phenanthridines / Q000494:pharmacology; D010716:Phosphatidylinositols / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017473:Receptors, Opioid, kappa / Q000037:antagonists & inhibitors / Q000502:physiology*; D010566:Virulence Factors, Bordetella / Q000494:pharmacology*
D000470:Alkaloids; D044482:Benzeneacetamides; D053119:Benzophenanthridines; D002712:Chlorides; D004723:Endorphins; D010617:Phenanthridines; D010716:Phosphatidylinositols; D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa; D010566:Virulence Factors, Bordetella; C051844:norbinaltorphimine; D009271:Naltrexone; D001285:Atropine; D004247:DNA; D008094:Lithium; C016299:chelerythrine; D037342:Pertussis Toxin; D011493:Protein Kinase C; D010744:Phosphoric Monoester Hydrolases; C021822:myo-inositol-1 (or 4)-monophosphatase; D019204:GTP-Binding Proteins; D018021:Lithium Chloride; C045444:U 69593