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：高灿 谌立伟 陶亦敏 陈洁 徐学军 池志强 

机构地区：[1]ShanghaiInstituteofMateriaMedica,ShanghaiInstitutesforBiologicalSciences,ChineseAcademyofSciences,Shanghai200031 [2]ResearchCenterforBiochemistryandMolecularBiology,XuzhouMedicalCollege,Xuzhou,Jiangsu221002,China

出　　处：《Acta Pharmacologica Sinica》2003年第12期1253-1258,共6页中国药理学报（英文版）

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 (25μmol/L, 15min) cAMP accumulation in a dose-dependent manner and this effect could be reversed by naloxone. F9202, F9204, and Mor could significantly increase CREB phosphorylation 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 Ca^2+/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.

关 键 词：羟甲芬太尼 立体异构体 细胞培养 海马 神经元 CAMP 反应元件结合蛋白 磷酸化 

分 类 号：R965[医药卫生—药理学]