Zhao Ping, Huang Yueming, Zuo Zhiyi
Department of Anesthesiology and Neuroscience, University of Virginia, Charlottesville, 22908-0710, USA.
J Neuropathol Exp Neurol. 2006 Oct;65(10):945-52. doi: 10.1097/01.jnen.0000235123.05677.4b.
We have shown that exposure of neurons to opioid immediately before ischemia induces ischemia tolerance. This phenomenon is called acute opioid preconditioning. In this study, we test the hypothesis that opioids induce delayed neuropreconditioning (from hours to days after opioid exposure). Exposure to morphine, an agonist for delta-, mu-, and kappa-opioid receptors, or Tan-67, a selective delta1-receptor agonist, for 30 minutes at 24 hours before a 35-minute oxygen-glucose deprivation (OGD, to simulate ischemia in vitro) dose-dependently reduced the OGD-induced neuronal death in the CA1 region of the rat organotypic hippocampal slice cultures. The morphine preconditioning-induced neuroprotection was inhibited by beta-funaltrexamine, a mu-opioid receptor antagonist, but not by 7-benzylidenenaltrexone, a delta1-receptor antagonist, or nor-binaltorphimine, a kappa-receptor antagonist. The Tan-67 preconditioning-induced neuroprotection was inhibited by 7-benzylidenenaltrexone. The combination of morphine and Tan-67 did not induce a better preconditioning effect than did morphine or Tan-67 alone. Application of morphine and Tan-67 at 24 hours before permanent right middle cerebral arterial occlusion reduced brain infarct volume and improved neurologic functional outcome assessed 24 hours after the occlusion in adult male rats. These results suggest that morphine and Tan-67 induce a delayed preconditioning effect in the brain under in vivo and in vitro conditions. Whereas the delayed phase of morphine preconditioning may involve mu-opioid receptors, Tan-67 preconditioning may be mediated by delta1-opioid receptors. Morphine and Tan-67 may activate a shared intracellular signaling pathway to induce the delayed preconditioning effects in the brain.
我们已经表明，在缺血前立即让神经元暴露于阿片类物质可诱导缺血耐受。这种现象被称为急性阿片类物质预处理。在本研究中，我们检验了阿片类物质诱导延迟性神经预处理（在阿片类物质暴露后数小时至数天）的假说。在35分钟氧糖剥夺（OGD，用于在体外模拟缺血）前24小时，将大鼠器官型海马脑片培养物的CA1区暴露于吗啡（一种δ、μ和κ阿片受体激动剂）或Tan - 67（一种选择性δ1受体激动剂）30分钟，剂量依赖性地减少了OGD诱导的神经元死亡。吗啡预处理诱导的神经保护作用被μ阿片受体拮抗剂β - 芬太尼环唑抑制，但未被δ1受体拮抗剂7 - 苄叉纳曲酮或κ受体拮抗剂去甲二丙诺啡抑制。Tan - 67预处理诱导的神经保护作用被7 - 苄叉纳曲酮抑制。吗啡和Tan - 67联合应用并未比单独使用吗啡或Tan - 67诱导出更好的预处理效果。在成年雄性大鼠永久性右侧大脑中动脉闭塞前24小时应用吗啡和Tan - 67，可减少脑梗死体积，并改善闭塞后24小时评估的神经功能结局。这些结果表明，吗啡和Tan - 67在体内和体外条件下均可在脑中诱导延迟预处理效应。吗啡预处理的延迟阶段可能涉及μ阿片受体，而Tan - 67预处理可能由δ1阿片受体介导。吗啡和Tan - 67可能激活共同的细胞内信号通路以在脑中诱导延迟预处理效应。
