OPIOIDS AND CELLULAR SURVIVAL

本项目研究δ阿片肽DADLE在细胞存活中的生理作用和潜在的生化机制。 在本财政年度，我们发现DADLE在体外和体内增强大鼠胚胎多巴胺能神经元的存活。 DADLE预处理的胚胎多巴胺能细胞移植到6-OHDA损伤的大鼠体内，可促进这些细胞的存活。 在甲基苯丙胺（METH）研究中，我们发现施用单次高剂量的METH（25 mg/kg，i. p.）能够引起纹状体多巴胺的几乎完全耗尽以及纹状体处的多巴胺转运体（DAT）和酪氨酸羟化酶（TH）的接近50%的损失。 单次施用DADLE（20 mg/kg，i. p.），在METH前30 min给予，可完全阻断DAT和TH的丢失，部分阻断METH引起的多巴胺耗竭。 受METH影响的肿瘤坏死因子p53的基因表达也被DADLE阻断。 最后，我们发现DADLE可以防止由METH引起的DAT和TH功能的丧失。 因此，内源性阿片肽可能在细胞抵抗某些精神兴奋剂和神经毒性药物引起的神经毒性中起重要作用。

This project examines the physiological effects and the underlying biochemical mechanisms of the action of delta opioid peptide DADLE in cell survival. In this fiscal year, we found that DADLE enhances the survival of rat embryonic dopaminergic neurons in vitro and in vivo. Embryonic dopaminergic cells pretreated with DADLE promote the survival of those cells when transplanted into the 6-OHDA lesioned rats. In the methamphetamine (METH) studies, we found that administration of a single high dose of METH (25 mg/kg, i.p.) was able to cause a near complete depletion of striatal dopamine and a close to 50% loss of dopamine transporters (DAT) and tyrosine hydroxylase (TH)at the striatum. A single administration of DADLE (20 mg/kg, i.p.), given 30 min before METH, completely blocked the loss of DAT and TH, and partially blocked the depletion of dopamine caused by METH. The gene expression of a tumor necrosis factor p53 affected by METH was also blocked by DADLE. Finally, we found that DADLE can prevent the the functional loss of DAT and TH caused by METH. Thus, endogenous opioid peptide may play important role in cell survival against neurotoxicity caused by certain psychostimulants and neurotoxic agents.