Vagal afferents play a role in gut - brain signaling of physiological and pathological stimuli. Here we investigated how backdiffusion of luminal HCl or NH₄OH and pentagastrin-stimulated acid secretion interact in the communication between rat stomach and brainstem. Rats were pretreated intraperitoneally with vehicle or appropriate doses of cimetidine, omeprazole, pentagastrin, dexloxiglumide (CCK₁ receptor antagonist) and itriglumide (CCK₂ receptor antagonist) before intragastric administration of saline or backdiffusing concentrations of HCl or NH₄OH. Two hours later neuronal activation in the nucleus tractus solitarii (NTS) and area postrema was visualized by c-Fos immunohistochemistry. Exposure of the rat gastric mucosa to HCl (0.15 - 0.5 M) or NH₄OH (0.1 - 0.3 M) led to a concentration-dependent expression of c-Fos in the NTS, which was not related to gender, gastric mucosal injury or gastropyloric motor alterations. The c-Fos response to HCl was diminished by cimetidine and omeprazole, enhanced by pentagastrin and left unchanged by dexloxiglumide and itriglumide. Pentagastrin alone caused an omeprazole-resistant expression of c-fos which in the NTS was attenuated by itriglumide and prevented by dexloxiglumide but in the area postrema was reduced by dexloxiglumide and abolished by itriglumide. We conclude that vagal afferents transmit physiological stimuli (gastrin) and pathological events (backdiffusion of luminal HCl or NH₄OH) from the stomach to the brainstem. These communication modalities interact because, firstly, acid secretion enhances afferent signaling of gastric acid backdiffusion and, secondly, gastrin activates NTS neurons through stimulation of CCK₁ receptors on vagal afferents and of CCK₂ receptors on area postrema neurons projecting to the NTS.