ABSTRACT Many gastrointestinal stimuli result in gastric fundic relaxation. This information is integrated at the interface of vagal afferents and efferents in the dorsal vagal complex. Substance P (SP) is present in this region, and the neurokinin 1 receptor (NK 1 R) is highly expressed in preganglionic neurons of the dorsal motor nucleus of the vagus (DMN). However, its functional effects on vagal motor output to the stomach have not been investigated. Therefore, we determined the gastric motor effects of stereotaxic microinjection of SP and selective tachykinin receptor agents into the DMN of anesthetized rats. Dose-related decreases in intragastric pressure and antral motility were obtained on the microinjection of SP (135 and 405 pmol) into the DMN, without cardiovascular changes. Similar decreases in intragastric pressure were noted after the microinjection of [Sar 9 ,Met(O 2 ) 11 ]SP (NK 1 R agonist; 135 pmol) but not senktide (NK 3 R agonist; 135 pmol) or vehicle. The gastric motor inhibition evoked by SP (135 pmol) was attenuated by prior microinjection of 2-methoxy-5-tetrazol-1-yl-benzyl-(2-phenyl-piperidin-3-yl)-amine (GR203040; 1 nmol; NK 1 R antagonist). Vagotomy or hexamethonium (15 mg/kg i.v.) completely abolished the gastric relaxation evoked by SP (135 pmol) microinjected into the DMN. We conclude that SP acts on NK 1 R preganglionic cholinergic vagal neurons in the DMN, which control enteric nonadrenergic noncholinergic motor inhibition of the fundus. The potential relevance is that an antiemetic site of action of NK 1 R antagonists may be in the DMN to prevent excitation of neurons controlling fundic relaxation, which is an essential prodromal component of emesis. Many stimuli to the gastrointestinal tract result in hormonal ("endoneurocrine") or neuronal feedback to other regions of the gut, and the vagus nerve is intimately involved in conveying this information to the upper gastrointestinal tract. Integration of "long-loop" vagal afferent-efferent pathways from the gut occurs in the dorsal vagal complex of the hindbrain medulla. This complex comprises the dorsal motor nucleus of the vagus (DMN), where preganglionic motor neurons innervating the gastrointestinal tract are located, and the nucleus tractus solitarius, where primary visceral afferents terminate. Preganglionic neurons in the DMN target the stomach One candidate neurotransmitter in the dorsal vagal complex that could mediate fundic relaxation is substance P (SP). The microinjection of SP into the nucleus tractus solitarius evokes gastric relaxatio
