In this study, we evaluated the role of orexin receptors in the dorsal hippocampus (dHPC) in the development of morphine-induced conditioned place preference (CPP) and modification of hippocampal c-Fos and cyclic AMP response element-binding protein (CREB) levels. Orexin-A (0.5, 5, and 50 pmol) and the orexin-1 receptor antagonist, SB334867 (10, 20, and 40 nmol), were bilaterally infused into the dHPC immediately before conditioning with morphine (0.5 or 7.5 mg/kg) using the CPP task. Western blotting was then used to measure the protein levels of c-Fos, total CREB, and phosphorylated CREB (pCREB) in the hippocampus. Orexin did not enhance the rewarding efficacy of morphine (0.5 mg/kg), but caused a reduction in hippocampal c-Fos. Successful conditioning with morphine (7.5 mg/kg) was associated with increased levels of hippocampal c-Fos and CREB, but with decreased CREB phosphorylation. Intrahippocampal administration of SB334867 before conditioning sessions disrupted the rewarding effect of morphine (7.5 mg/kg) and blocked morphine-induced increases in hippocampal CREB protein levels. The results suggest that orexin signaling within the dHPC is necessary for the development of morphine CPP. Morphine reward is related to altered levels of hippocampal c-Fos and CREB. Inhibition of morphine-induced increases in CREB levels might be the underlying mechanism for the disruption of morphine CPP.