We have investigated the pathway and the mechanism by which cholecystokinin octapeptide (CCK-8), given systemically, may influence the discharge of brain stem neurons that have an input from the stomach. Extracellular recordings were made from neurons in the nucleus of the solitary tract (NTS), where vagal afferents terminate, and from neighboring regions of the dorsal medial medulla. Gastric distension and CCK-8 injected intra-aortically close to the stomach evoked either excitatory or inhibitory responses that were abolished by cervical vagal section. In animals from which the celiac/superior mesenteric ganglia were removed, or the gastric antrum resected 2 weeks earlier, responses to gastric distension and CCK-8 were maintained. The effects of CCK-8 are unlikely to be secondary to changes in smooth muscle tone because CCK-8 decreased pressure in the body of the stomach, while distension increased it. Moreover, intravenous noradrenaline and vasoactive intestinal peptide had effects similar to CCK-8 on intragastric pressure, but evoked different patterns of responses from brain stem neurons. The results are consistent with the idea that CCK-8 acts directly on vagal mechanoreceptive endings in the gastric corpus wall. It is well known that peripheral administration of CCK-8 influences short-term regulation of food intake. The effects described here may reflect the pathway by which peripheral CCK influences CNS function.