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 neurokinin1 receptor (NK1R) 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 [Sar9,Met(O2)11]SP (NK1R agonist; 135 pmol) but not senktide (NK3R 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; NK1R 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 NK1R 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 NK1R antagonists may be in the DMN to prevent excitation of neurons controlling fundic relaxation, which is an essential prodromal component of emesis.
Footnotes
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Send reprint requests to: Dr. P. Hornby, Department of Pharmacology, Louisiana State University Health Sciences Center, 1901 Perdido St., New Orleans, LA 70112. E-mail:phornb{at}lsumc.edu
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↵1 This work was supported by a grant from Glaxo-Wellcome and by U.S. Public Health Service Grant DK42714 to P.J.H.
- Abbreviations:
- DMN
- dorsal motor nucleus of the vagus
- AUC
- area under the curve
- IgP
- intragastric pressure
- NANC
- nonadrenergic noncholinergic
- NO
- nitric oxide
- nAmb
- nucleus ambiguus
- NK1R
- neurokinin1 receptor
- SP
- substance P
- Received September 7, 1999.
- Accepted December 20, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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