Barg J, Belcheva M M, Coscia C J
E. A. Doisy Department of Biochemistry and Molecular Biology, St. Louis University School of Medicine, Missouri 63104-1079.
J Neurochem. 1992 Sep;59(3):1145-52. doi: 10.1111/j.1471-4159.1992.tb08357.x.
An opioid receptor agonist, [D-Ala2,Me-Phe4,Glyol5]enkephalin (DAMGE), decreased [3H]thymidine incorporation into DNA of fetal rat brain cell aggregates. This action proved to depend on the dose of this enkephalin analog and the interval the aggregates were maintained in culture. The opioid antagonist naltrexone and the mu-specific antagonist cyclic D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr amide (CTOP) reversed the DAMGE effect, arguing for a receptor-mediated mechanism. The mu-opioid nature of this receptor was further established by inhibiting DNA synthesis with the highly mu-selective agonist morphiceptin and blocking its action with CTOP. Several other opioids, pertussis toxin, and LiCl also diminished DNA synthesis, whereas cholera toxin elicited a modest increase. Naltrexone completely reversed the inhibition elicited by the combination of DAMGE and low doses of LiCl but not by that of high levels of LiCl alone. The enkephalin analog also reduced basal [3H]inositol trisphosphate and glutamate-stimulated [3H]inositol monophosphate and [3H]inositol bisphosphate accumulation in the aggregates. These DAMGE effects were reversed by naltrexone and were temporally correlated with the inhibition of DNA synthesis. A selective protein kinase C inhibitor, chelerythrine, also inhibited thymidine incorporation dose-dependently. The effect of DAMGE was not additive in the presence of chelerythrine but appeared to be consistent with their actions being mediated via a common signaling pathway. These results suggest the involvement of the phosphoinositol signal transduction system in the modulation of thymidine incorporation into DNA by DAMGE.
一种阿片受体激动剂，[D-丙氨酸2，甲基苯丙氨酸4，甘油5]脑啡肽（DAMGE），可减少[3H]胸腺嘧啶核苷掺入胎鼠脑细胞聚集体的DNA中。这一作用被证明取决于这种脑啡肽类似物的剂量以及聚集体在培养中维持的时间间隔。阿片拮抗剂纳曲酮和μ特异性拮抗剂环D-苯丙氨酸-半胱氨酸-酪氨酸-D-色氨酸-鸟氨酸-苏氨酸-苯丙氨酸-苏氨酸酰胺（CTOP）可逆转DAMGE的作用，这表明存在受体介导的机制。通过用高度μ选择性激动剂吗啡肽抑制DNA合成并用CTOP阻断其作用，进一步证实了该受体的μ阿片性质。其他几种阿片类药物、百日咳毒素和氯化锂也可减少DNA合成，而霍乱毒素则引起适度增加。纳曲酮可完全逆转DAMGE与低剂量氯化锂联合引起的抑制作用，但不能逆转单独高剂量氯化锂引起的抑制作用。脑啡肽类似物还可降低聚集体中基础[3H]肌醇三磷酸以及谷氨酸刺激的[3H]肌醇单磷酸和[3H]肌醇二磷酸的积累。这些DAMGE的作用可被纳曲酮逆转，并且在时间上与DNA合成的抑制相关。一种选择性蛋白激酶C抑制剂白屈菜红碱也剂量依赖性地抑制胸腺嘧啶核苷掺入。在存在白屈菜红碱的情况下，DAMGE的作用没有叠加，但似乎与它们通过共同信号通路介导的作用一致。这些结果表明磷酸肌醇信号转导系统参与了DAMGE对胸腺嘧啶核苷掺入DNA的调节。
