侧脑室注射八肽胆囊收缩素及其受体拮抗剂对吗啡依赖大鼠戒断症状的影响  

Effects of CCK-8 and its receptor antagonists given intracerebroventricularly on withdrawal symptom of morphine dependent rats

作　　者：文迪[1] 马春玲[1] 丛斌[1] 张雅静[1,2] 杨胜昌[1] 孟雁欣[1] 于峰[1] 倪志宇[1] 李淑瑾[1] 

机构地区：[1]河北医科大学基础医学院法医学系河北省法医学重点实验室,河北石家庄050017 [2]石家庄市第一医院,河北石家庄050011

出　　处：《中国药理学通报》2011年第10期1363-1368,共6页Chinese Pharmacological Bulletin

基　　金：国家自然科学基金资助项目(No81172900;30672355);河北省自然科学基金资助项目(NoC2007000826);河北省应用基础研究重点基础研究资助项目(No10966911D)

摘　　要：目的观察侧脑室给予八肽胆囊收缩素(CCK-8)及其受体拮抗剂慢性干预对吗啡依赖大鼠戒断症状的影响,并在体外观察CCK-8对μ阿片受体结合反应的影响,初步探讨CCK-8对吗啡依赖过程的影响及其相关受体机制。方法建立大鼠吗啡依赖及纳络酮催促戒断模型,侧脑室注射CCK-8及CCK1受体拮抗剂devazepide、CCK2受体拮抗剂LY-288,513慢性干预,观察其对戒断症状的影响;应用放射配基结合实验体外检测CCK-8对μ阿片受体结合特征的影响。结果①吗啡注射前10 min侧脑室注射CCK-8和CCK受体拮抗剂devazepide、LY-288,513慢性干预均能降低吗啡依赖大鼠的戒断症状评分,并可明显改善体重下降、跳跃、齿颤、流涎等戒断症状,与戒断组相比差异均有显著性(P<0.01);②10-8～10-6 mol.L-1 CCK-8可以剂量依赖性地抑制大鼠脑组织中μ阿片受体与其配基的结合(P<0.01),降低μ阿片受体结合反应的Bmax值,而对Kd值无影响;且此抑制作用可被CCK1及CCK2受体拮抗剂翻转(P<0.01)。结论 CCK-8及其受体拮抗剂慢性干预均能减轻吗啡依赖大鼠戒断症状;CCK-8通过抑制μ阿片受体与其配基的结合,降低μ阿片受体的Bmax值,发挥其"抗阿片作用"。Aim To explore the mechanisms of CCK-8 in morphine dependence development,the effect of CCK-8 and CCK receptor antagonists on morphine withdrawal rats was observed.Meanwhile,the effect of CCK-8 on binding affinity of μ-opioid receptor was detected.Methods After rats models were established for morphine dependence and naloxone-precipitated withdrawal,the effects of CCK-8,devazepide,a CCK1 receptor antagonist and LY-288,513,a CCK2 receptor antagonist given intracerebroventricularly on the morphine withdrawal symptom were observed,and the effects of CCK-8 on binding affinity of μ-opioid receptor were tested with radioligand binding assay.Results ① Intracerebroventricular injections of CCK-8 and CCK receptor antagonists 10 min before morphine treatments were able to drop the overall morphine withdrawal scores,and attenuated the symptoms of weight loss,jumping,teeth chattering and ptosis.② 10-8~10-6 mol·L-1 CCK-8 suppressed dose-dependently the binding of MOR,and significantly decreased the binding capacity（Bmax）,but not the binding affinity（Kd）.Furthermore,this effect could be reversed by CCK1 and CCK2 receptor antagonists.Conclusion Both CCK-8 and CCK receptor antagonists can alleviate withdrawal symptoms of morphine dependent rats,and CCK-8 exerts its anti-opioid effects by suppressing the binding of μ-opioid receptor and by decreasing the Bmax of μ-opioid receptor.

关 键 词：法医毒理学 吗啡依赖 戒断症状 八肽胆囊收缩素 CCK受体拮抗剂 Μ阿片受体 

分 类 号：R-332[医药卫生] R392.11