kappa-Opioid agonist modulation of [3H]thymidine incorporation into DNA: evidence for the involvement of pertussis toxin-sensitive G protein-coupled phosphoinositide turnover

J Neurochem. 1993 Apr;60(4):1505-11. doi: 10.1111/j.1471-4159.1993.tb03314.x.

Abstract

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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alkaloids
  • Animals
  • Atropine / pharmacology
  • Autoradiography
  • Benzeneacetamides*
  • Benzophenanthridines
  • Brain / drug effects
  • Brain / embryology*
  • Brain / metabolism
  • Chlorides / pharmacology
  • DNA / biosynthesis*
  • Endorphins / pharmacology*
  • GTP-Binding Proteins / physiology*
  • Lithium / pharmacology
  • Lithium Chloride
  • Naltrexone / analogs & derivatives
  • Naltrexone / pharmacology
  • Pertussis Toxin*
  • Phenanthridines / pharmacology
  • Phosphatidylinositols / metabolism*
  • Phosphoric Monoester Hydrolases / antagonists & inhibitors
  • Protein Kinase C / antagonists & inhibitors
  • Pyrrolidines / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Opioid, kappa / antagonists & inhibitors
  • Receptors, Opioid, kappa / physiology*
  • Virulence Factors, Bordetella / pharmacology*

Substances

  • Alkaloids
  • Benzeneacetamides
  • Benzophenanthridines
  • Chlorides
  • Endorphins
  • Phenanthridines
  • Phosphatidylinositols
  • Pyrrolidines
  • Receptors, Opioid, kappa
  • Virulence Factors, Bordetella
  • norbinaltorphimine
  • Naltrexone
  • Atropine
  • DNA
  • Lithium
  • chelerythrine
  • Pertussis Toxin
  • Protein Kinase C
  • Phosphoric Monoester Hydrolases
  • myo-inositol-1 (or 4)-monophosphatase
  • GTP-Binding Proteins
  • Lithium Chloride
  • U 69593