Dynorphins modulate DNA synthesis in fetal brain cell aggregates.
Previously, opioid peptide analogues, beta-endorphin, and synthetic opiates were found to inhibit DNA synthesis in 7-day fetal rat brain cell aggregates via kappa- and mu-opioid receptors. Here dynorphins and other endogenous opioid peptides were investigated for their effect on DNA synthesis in rat and guinea pig brain cell aggregates. At 1 microM, all dynorphins tested and beta-endorphin inhibited [3H]thymidine incorporation into DNA by 20-38% in 7-day rat brain cell aggregates. The putative epsilon-antagonist beta-endorphin (1-27) did not prevent the effect of beta-endorphin, suggesting that the epsilon-receptor is not involved in opioid inhibition of DNA synthesis. The kappa-selective antagonist norbinaltorphimine blocked dynorphin A or B inhibition of DNA synthesis, implicating a kappa-opioid receptor. In dose-dependency studies, dynorphin B was three orders of magnitude more potent than dynorphin A in the attenuation of thymidine incorporation, indicative of the mediation of its action by a discrete kappa-receptor subtype. The IC50 value of 0.1 nM estimated for dynorphin B is in the physiological range for dynorphins in developing brain. In guinea pig brain cell aggregates, the kappa-receptor agonists U50488, U69593, and dynorphin B reduced thymidine incorporation by 40%. When 21-day aggregates were treated with dynorphins, a 33-86% enhancement of thymidine incorporation was observed. Because both 7- and 21-day aggregates correspond to stages in development when glial cell proliferation is prevalent and glia preferentially express kappa-receptors in rat brain, these findings support the hypothesis that dynorphins modulate glial DNA synthesis during brain ontogeny.
Gorodinsky
A
A
Department of Biochemistry and Molecular Biology, St. Louis University School of Medicine, MO 63104-1079, USA.
Barg
J
J
Belcheva
M M
MM
Levy
R
R
McHale
R J
RJ
Vogel
Z
Z
Coscia
C J
CJ
D000818:Animals; D001921:Brain / Q000196:embryology*; D002449:Cell Aggregation; D004247:DNA / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D004399:Dynorphins / Q000494:pharmacology / Q000502:physiology*; D005333:Fetus / Q000166:cytology / Q000378:metabolism*; D010446:Peptide Fragments / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013936:Thymidine / Q000037:antagonists & inhibitors / Q000378:metabolism
D010446:Peptide Fragments; D004399:Dynorphins; D004247:DNA; D013936:Thymidine