BACKGROUND Orexin-A is a novel peptide that appears to play a role in regulation of gastric acid secretion. However, little is known about sites of its action. In addition, evidences suggest that some of orexin-A neurons respond to glucose. In this study, we address the hypothesis which demonstrates that orexin-A and glucose act in the hypothalamic paraventricular nucleus (PVN) to increase gastric acid secretion and juice volume in pyloric-ligated conscious rats. METHODS Male Wistar rats were implanted with guide canula directed to the PVN. Orexin-A (3-10 μg), glucose (350-750 ng) SB334867 (6-20 μg) were microinjected. The effect of pretreatment with an orexin-1 receptor antagonist, SB334867, on orexin-A and D-glucose induced acid secretion was assessed. Gastric acid secretion was measured using the pylorus-ligation method, and the amount of gastric acid was determined by titration with 0.01 N NaOH to a pH of 7.0. RESULTS Intraparaventricular injection of orexin-A or D-glucose stimulated gastric acid secretion in a dose-dependent manner. The PVN injections of orexin-A receptor antagonist, SB334867, were associated with gastric acid secretion decrease and inhibited effects of PVN-injected orexin-A. Orexin-stimulated gastric acid secretion was decreased (~40%) after PVN lesions. Glucose-stimulated gastric acid secretion was also suppressed by intraperitoneal (IP) injection of SB334867. In addition, it was observed that co-injection of orexin-A and glucose at ineffective doses increased gastric secretion significantly. CONCLUSIONS We suggest that orexin-A and glucose effects on the PVN stimulate gastric acid secretion. This stimulatory effect is probably mediated by orexin-1 receptors.