The actions of cholecystokinin (CCK) on gastrointestinal functions occur mainly via paracrine effects on peripheral sensory vagal fibers, which engage vago-vagal brainstem circuits to convey effector responses back to the gastrointestinal tract. Recent evidence suggests, however, that CCK also affects brainstem structures directly. Many electrophysiological studies, including our own, have shown that brainstem vagal circuits are excited by sulfated CCK (CCK-8s) directly, and we have further demonstrated that CCK-8s induces a remarkable degree of plasticity in GABAergic brainstem synapses. In the present study, we used fasted, anesthetized Sprague-Dawley rats to investigate the effects of brainstem administration of CCK-8s on gastric tone before and after activation of the esophageal-gastric reflex. CCK-8s microinjected in the dorsal vagal complex (DVC) or applied on the floor of the 4^th ventricle induced an immediate and transient decrease in gastric tone. Upon recovery of gastric tone to baseline values, the gastric relaxation induced by esophageal distention was attenuated or even reversed. The effects of CCK-8s were antagonized by vagotomy or 4^th ventricular, but not intravenous, administration of the CCK-A antagonist lorglumide, suggesting a peripheral, not central, site of action. The gastric relaxation induced by DVC microinjection of CCK-8s microinjection was unaffected by pretreatment with systemic bethanecol but was completely blocked by L-NAME. These data suggest that 1) brainstem application of CCK-8s induces a vagally-mediated gastric relaxation; 2) the CCK-8s induced gastric relaxation is mediated via activation of NANC pathways; and, 3) CCK-8s reverses the esophageal-gastric reflex transiently.