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. BR>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. BR>