K-Opioid Agonist Modulation of [3H]Thymidine Incorporation into DNA: Evidence for the Involvement of Pertussis Toxin-Sensitive G Protein-Coupled Phosphoinositide Turnover

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Abstract
A body of evidence has indicated that μ‐opioid agonists can inhibit DNA synthesis in developing brain. We now report that K‐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. K agonists decreased thymidine incorporation by 35% in cultures grown for 7 days, and this process was reversed by the K‐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 K‐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 norbin‐altorphimine. Pertussis toxin blocked U69593‐mediated inhibition of DNA synthesis. The action of K 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 K 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.