Opioids And Cellular Survival

本项目研究了Delta阿片肽DADLE在细胞存活中的生理作用和潜在的生化机制。神经营养因子，包括神经生长因子(NGF)，在神经元的发育和存活中发挥着重要作用。已知阿片类药物会影响神经元发育。因此，有报道称阿片类激动剂和拮抗剂调节新生啮齿动物大脑中的NGF水平。例如，阿片类拮抗剂纳曲酮增加了新生大鼠纹状体内NGF的水平。另一方面，美沙酮和丁丙诺啡等阿片激动剂被报道可降低新生大鼠纹状体中NGF的水平。然而，据我们所知，阿片类药物对成年动物大脑中NGF水平的影响尚未见报道。因此，由于DADLE在成年动物中具有神经保护作用，而且神经营养因子在大脑中具有神经保护作用，我们研究了DADLE是否会影响成年CD-1小鼠的神经营养因子水平，包括NGF和GDNF。在这里，我们发现慢性治疗DADLE导致成年白化瑞士(CD-1)小鼠海马区和中脑神经生长因子(NGF)显著增加，但在纹状体或额叶皮质没有。胶质细胞源性神经营养因子(GDNF)未受明显影响。因此，DADLE的神经保护作用可能部分由NGF介导。

This project examines the physiological effects and the underlying biochemical mechanisms of the action of delta opioid peptide DADLE in cellular survival. Neurotrophic factors, including the nerve growth factor (NGF), are known to play important roles in the development and survival of neurons. Opioids have been known to affect neuronal development. Thus, there were reports that opioid agonists and antagonists regulate NGF levels in the neonatal rodent brain. For example, opioid antagonist naltrexone increased the level of NGF in the striatum of neonatal rats. On the other hand, the opioid agonists like methadone and buprenorphine were reported to reduce the level of NGF in the striatum of newborn rats. However, to our knowledge, the effect of opioids on NGF levels in the brain of adult animals has never been reported. Thus, because DADLE is neuroprotective in adult animals and because neurotrophic factors are neuroprotective in the brain, we examined if DADLE may affect the level of neurotrophic factors including NGF and GDNF in adult CD-1 mice. Here we found that chronic treatment of DADLE caused a significant increase of nerve growth factor (NGF) in the hippocampus and the mid-brain of adult albino Swiss (CD-1) mice, but not in the striatum or frontal cortex. The glia-derived neurotrophic factor (GDNF) was not significantly affected. Thus, the neuroprotective action of DADLE may be mediated in part by NGF.