OPIOIDS AND CELLULAR SURVIVAL

本项目探讨了delta阿片肽DADLE在细胞存活中的生理作用和潜在的生化机制。本财年，我们发现DADLE在体外和体内均能提高大鼠胚胎多巴胺能神经元的存活率。经DADLE预处理的胚胎多巴胺能细胞移植到6-OHDA损伤大鼠体内后，可促进这些细胞的存活。在甲基苯丙胺（冰毒）研究中，我们发现单次高剂量冰毒（25mg /kg, i.p.d.）能够导致纹状体多巴胺几乎完全消耗，纹状体多巴胺转运体（DAT）和酪氨酸羟化酶（TH）损失接近50%。在冰毒前30分钟单次给予DADLE (20 mg/kg, ig)，完全阻断了DAT和TH的丢失，部分阻断了冰毒引起的多巴胺的消耗。受甲基安非他明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可以预防甲基苯丙胺引起的DAT和TH的功能丧失。因此，内源性阿片肽可能在抗某些精神兴奋剂和神经毒性药物引起的细胞存活中起重要作用。

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.