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目的研究胆囊收缩素(CCK)受体拮抗剂对吗啡戒断大鼠海马神经元CaMKⅡαmRNA及蛋白表达的影响,进一步探讨CCK受体拮抗剂抑制吗啡戒断症状的作用机制。方法应用剂量递增法皮下注射盐酸吗啡,建立大鼠吗啡躯体依赖模型,将模型鼠的海马组织制成细胞悬液,体外给予不同剂量CCK-A及CCK-B受体拮抗剂,采用RT-PCR和western blot技术分别检测海马神经元CaMKⅡα的mRNA及蛋白表达。结果①慢性吗啡成瘾大鼠海马神经元CaMKⅡα mRNA及蛋白表达与对照组相比均显著增高;②成瘾大鼠海马神经元细胞在给予纳洛酮催促戒断后,与对照组及吗啡组相比,CaMKⅡα mRNA及蛋白均显著降低;③纳洛酮催促戒断组加入不同剂量的CCK-A受体拮抗剂(CR-1409)、CCK-B受体拮抗剂(CR-2945),CaMKⅡα mRNA及蛋白表达与纳洛酮组相比显著升高,并随浓度的升高而升高,两种拮抗剂的作用以CR-2945起主要作用。结论CCK-A、CCK-B受体拮抗剂可以有效地抑制因纳洛酮催促戒断所引起的CaMKⅡα mRNA及蛋白表达降低,并具有剂量依赖性。
Objective To investigate the effect of cholecystokinin (CCK) receptor antagonist on the expression of CaMKⅡα mRNA and protein in hippocampal neurons of morphine withdrawal rats and to explore the mechanism of CCK receptor antagonist inhibiting morphine withdrawal symptoms. Methods Morphine hydrochloride was injected subcutaneously into rats by dose escalation. The morphine-dependent model of morphine was established. The hippocampal tissue of the model mice was made into cell suspension. CCK-A and CCK-B receptor antagonists were administered in vitro at different doses. RT- And western blot were used to detect the mRNA and protein expression of CaMKⅡα in hippocampal neurons respectively. Results ① The expression of CaMKⅡα mRNA and protein in hippocampal neurons of chronic morphine-addicted rats were significantly increased compared with the control group. ② After addicted to naloxone, the neurons in hippocampus of addicted rats were abstinent from the control and morphine groups (P <0.05) .③Naloxone induced withdrawal of CCK-A receptor antagonist (CR-1409), CCK-B receptor antagonist (CR-2945), CaMKⅡα mRNA and protein expression was significantly increased compared with naloxone group, and with the concentration increased, the role of two antagonists CR-2945 play a major role. Conclusion CCK-A and CCK-B receptor antagonists can effectively inhibit the decrease of CaMKⅡα mRNA and protein expression induced by withdrawal of naloxone in a dose-dependent manner.