DYNORPHINS MODULATE DNA-SYNTHESIS IN FETAL BRAIN-CELL AGGREGATES

Previously, opioid peptide analogues, beta-endorphin, and synthetic op iates were found to inhibit DNA synthesis in 7-day fetal rat brain cel l aggregates via kappa-and mu-opioid receptors. Here dynorphins and ot her endogenous opioid peptides were investigated for their effect on D NA synthesis in rat and guinea pig brain cell aggregates. At 1 mu M, a ll dynorphins tested and beta-endorphin inhibited [H-3]thymidine incor poration into DNA by 20-38% in 7-day rat brain cell aggregates. The pu tative epsilon-antagonist beta-endorphin (1-27) did not prevent the ef fect of beta-endorphin, suggesting that the epsilon-receptor is not in volved in opioid inhibition of DNA synthesis. The kappa-selective anta gonist norbinaltorphimine blocked dynorphin A or B inhibition of DNA s ynthesis, implicating a kappa-opioid receptor. In dose-dependency stud ies, dynorphin B was three orders of magnitude more potent than dynorp hin A in the attenuation of thymidine incorporation, indicative of the mediation of its action by a discrete kappa-receptor subtype, The IC5 0 value of 0.1 nM estimated for dynorphin B is in the physiological ra nge for dynorphins in developing brain. In guinea pig brain cell aggre gates, the kappa-receptor agonists U50488, U69593, and dynorphin B red uced thymidine incorporation by 40%. When 21-day aggregates were treat ed with dynorphins, a 33-86% enhancement of thymidine incorporation wa s observed. Because both 7- and 21-day aggregates correspond to stages in development when glial cell proliferation is prevalent and glia pr eferentially express kappa-receptors in rat brain, these findings supp ort the hypothesis that dynorphins modulate glial DNA synthesis during brain ontogeny.