八肽胆囊收缩素对吗啡戒断大鼠蓝斑和中脑导水管周围灰质CREB及p-CREB的影响

目的 探讨八肽胆囊收缩素（CCK-8）及其受体拮抗剂对吗啡戒断症状的影响及其相应的信号转导机制。方法 建立吗啡依赖及戒断动物模型，每组6只。应用改良柳田知司法对戒断症状评分，并采用免疫组织化学方法检测大鼠蓝斑和中脑导水管周围灰质内CREB及p-CREB的变化。结果 腹腔及侧脑室注射CCK-8，CCK1及CCK2受体拮抗剂均可明显降低戒断症状评分；吗啡依赖后蓝斑和中脑导水管内p-CREB明显增高，戒断后蓝斑内p-CREB水平较依赖组进一步增高，而中脑导水管内p-CREB却较依赖组下降。腹腔及侧脑室注射CCK-8，CCK1及CCK2受体拮抗剂均可逆转戒断后中脑导水管内p-CREB的降低；腹腔及侧脑室注射CCK1 及CCK2受体拮抗剂可逆转戒断后蓝斑内p-CREB的升高，而CCK-8却对蓝斑内p-CREB的表达无明显影响。结论 CCK-8可通过对蓝斑和中脑导水管内p-CREB的调节减轻吗啡戒断症状，且表现出明显的脑区特异性。

Effect of cholecystokinin octapeptide-8 on CREB and p-CREB in locus caeruleus and periaoueductal gray matter of morphine withdrawal rats

Objective To explore the effect of cholecystokinin octapeptide-8 (CCK-8) and its recepetor antagonists on morphine withdrawal and its signal transduction pathway.Methods Morphine dependent and withdrawal animal models were established, 6 rats for each group. Morphine withdrawal syndrome was observed and estimated by Gellert-Holtzman scale. The changes of CREB and p-CREB in the locus caeruleus (LC) and periaoueductal gray matter (PAG) were measured by immunohistochemical method. Results The withdrawal score was decreased by CCK-8 and its recepetor antagonists through intraperitoneal (i.p) or intracerebroventricular (i.v.c) injection. Chronic morphine treatment increased p-CREB in LC and PAG. After withdrawal, p-CREB was further increased in LC but decreased in PAG. CCK-8 and its recepetor antagonists by i.p or i.v.c reversed changes of p-CREB in PAG after withdrawal, CCK-8 recepetor antagonists by i.p or i.v.c reversed changes of p-CREB in LC after withdrawal but had no effect by CCK-8 Conclusion CCK-8 may inhibit the morphine withdrawal syndrome by modulating expression of p-CREB in LC and PAG, which is of obvious region-specificity.