羟甲芬太尼立体异构体对培养的海马神经元cAMP-反应元件结合蛋白磷酸化的影响

• 作者: 徐学军 池志强 谌立伟 陈洁 陶亦敏 高灿
• 来源期刊: 中国药理学报（英文版）
• 学科: 医学
• 关键词: ohmefentanyl stereoisomers cAMP-response element binding protein mu opioid receptor cyclic AMP hippocampal neurons phosphorylation
• 年，卷（期）: 2003,（12）
• 所属期刊栏目: 研究原著
• 页码范围: 1253-1258
• 页数: 6页
• 分类号: R97
• 语种: 英文

摘要

AIM: To define the effects and signal pathways of ohmefentanyl stereoisomers [(-)-cis-(3R,4S,2'R) OMF (F9202), (+)-cis-(3R, 4S, 2′S) OMF (F9204), and (-)-cis-(3S, 4S, 2′R) OMF (F9203)] on the phosphorylation of cAMP-re sponse element binding protein (CREB) in cultured rat hippocampal neurons. METHODS: The effects of the three OMF stereoisomers and morphine (Mor) on cAMP accumulation and CREB phosphorylation were monitored by radioimmunoassay and Western blot analysis, respectively. RESULTS: The three OMF stereoisomers and Mor could all partially inhibit forskolin-stimulated (25 μmol/L, 15 min) cAMP accumulation in a dose-dependent manner and this effect could be reversed by naloxone. F9202, F9204, and Mor could significantly increase CREB phospho rylation from 2.88 to 3.59 folds over control levels after 30-min exposure. This effect was reversed by naloxone,but F9203 failed to increase CREB phosphorylation. KN-62 and staurosporine significantly blocked the opioidsinduced CREB phosphorylation, while H-89 and PD 98059 had no effect on the actions. CONCLUSION: Mor,F9202, and F9204, which could induce psychological dependence affected via the μ-opioid receptor, stimulated intracellular signal pathways involving Ca2+/calmodulin-dependent protein kinases (CCDPK) and protein kinase C (PKC) pathways, which in turn initiated CREB phosphorylation. F9203, which could not induce dependence, had no effect on CREB phosphorylation in hippocampal neurons. The increased CREB phosphorylation in hippocampal neurons may play a role in opioids dependence.