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Dynorphins Modulate DNA Synthesis in Fetal Brain Cell Aggregates

1995; Wiley; Volume: 65; Issue: 4 Linguagem: Inglês

10.1046/j.1471-4159.1995.65041481.x

1471-4159

A. Gorodinsky, Jacob Barg, Mariana M. Belcheva, Rivka Levy, Robert J. McHale, Z. Vogel, Carmine Coscia,

Pharmacological Receptor Mechanisms and Effects

Abstract: Previously, opioid peptide analogues, β‐endorphin, and synthetic opiates were found to inhibit DNA synthesis in 7‐day fetal rat brain cell aggregates via κ‐and μ‐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 µ M , all dynorphins tested and β‐endorphin inhibited [ 3 H]thymidine incorporation into DNA by 20–38% in 7‐day rat brain cell aggregates. The putative ε‐antagonist β‐endorphin (1–27) did not prevent the effect of β‐endorphin, suggesting that the ε‐receptor is not involved in opioid inhibition of DNA synthesis. The κ‐selective antagonist norbinaltorphimine blocked dynorphin A or B inhibition of DNA synthesis, implicating a κ‐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 κ‐receptor subtype. The IC 50 value of 0.1 n M estimated for dynorphin B is in the physiological range for dynorphins in developing brain. In guinea pig brain cell aggregates, the κ‐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 κ‐receptors in rat brain, these findings support the hypothesis that dynorphins modulate glial DNA synthesis during brain ontogeny.