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目的:观察八肽胆囊收缩素(CCK-8)及其受体拮抗剂对吗啡戒断大鼠额叶皮质和海马cAMP反应元件结合蛋白(CREB)表达及其磷酸化(pCREB)的影响,初步探讨CCK-8调节吗啡戒断大鼠的受体后机制。方法:建立大鼠吗啡慢性依赖及纳络酮催促戒断模型,并给予CCK-8、CCK1受体拮抗剂L-364718和CCK2受体拮抗剂LY-288513慢性干预,应用Western blotting和免疫组织化学技术观察额叶皮质和海马CREB与pCREB表达的变化。结果:(1)正常组大鼠额叶皮质神经元胞浆、胞核均表达CREB蛋白,pCREB蛋白则仅在胞核中高表达;海马CA1区锥体细胞层神经元中,CREB蛋白在胞浆中高表达,胞核低表达,pCREB蛋白则仅在胞核中表达。(2)慢性吗啡作用后CREB无明显变化,pCREB增加;急性纳洛酮催促戒断后CREB仍无明显变化,pCREB进一步升高。(3)与戒断组相比,CCK-8、L-364718和LY-288513慢性干预对吗啡依赖戒断大鼠额叶皮质CREB蛋白表达无明显影响,pCREB蛋白表达均明显降低;L-364718和LY-288513慢性干预后,海马CREB与pCREB表达均明显降低,而CCK培慢性干预对CREB蛋白表达无明显影响,仅pCREB蛋白表达明显降低。结论:CCK-8及其受体拮抗剂可能通过调节核转录因子CREB减轻吗啡戒断症状,并具有脑区特异性。
AIM: To observe the effects of cholecystokinin octapeptide (CCK-8) and its receptor antagonist on cAMP response element binding protein (CREB) expression and phosphorylation (pCREB) in frontal cortex and hippocampus of morphine withdrawal rats. To investigate the mechanism of CCK-8 regulating the receptor in morphine withdrawal rats. Methods: Chronic dependence of morphine and withdrawal of naloxone were induced in rats. Chronic interventions of CCK-8, CCK1 receptor antagonist L-364718 and CCK2 receptor antagonist LY-288513 were established. Western blotting and immunohistochemistry Changes of CREB and pCREB expression in frontal cortex and hippocampus observed by technique. Results: (1) CREB protein was expressed in the cytoplasm and nucleus of normal rat cortical neurons while pCREB protein was only highly expressed in nucleus. In the hippocampal CA1 pyramidal neurons, CREB protein was found in cytoplasm High expression, low expression of nuclear, pCREB protein is only expressed in the nucleus. (2) There was no significant change of CREB and pCREB after chronic morphine treatment. There was no obvious change of CREB after acute naloxone withdrawal and the pCREB increased further. (3) Compared with the withdrawal group, the chronic intervention of CCK-8, L-364718 and LY-288513 had no significant effect on the expression of CREB protein in the frontal cortex of morphine-dependent withdrawal rats, and the expression of pCREB protein was significantly decreased; L-364718 After chronic intervention with LY-288513, the expression of CREB and pCREB in the hippocampus were significantly decreased. However, the chronic intervention of CCK did not affect the expression of CREB protein, but the expression of pCREB protein only decreased significantly. Conclusion: CCK-8 and its receptor antagonist may alleviate symptoms of morphine withdrawal by modulating the nuclear transcription factor CREB and have brain-region specificities.