Tachykinin NK(1)receptor-mediated inhibitory responses in the guinea-pig small intestine

We used in vivo, in vitro studies and immunohistochemistry to elucidate the mechanisms activated by tachykinin NK1 receptors in evoking inhibitory motor response in the guinea-pig small intestine. In vivo, the selective NK1 receptor agonist GR 73,632 produced a dose-dependent suppression of the distension-induced duodenal contractions, and a decrease of basal tone. These effects were reduced by pretreatment with the NK1 receptor antagonist SR 140,333. In L-Nω-nitro-L-arginine methylesther hydrochloride-pretreated animals, the suppressant effect of GR 73,632 on duodenal contractions was reduced, whereas the relaxation of the basal tone was unaffected. In vitro, GR 73,632 evoked a biphasic response consisting of a transient, tetrodotoxin- sensitive inhibitory effect followed by tetrodotoxin-resistant contractions. SR 140,333 blocked both inhibitory and excitatory motor responses induced by GR 73,632. NK1 immunoreactivity was localized to myenteric and submucosal neurons and to interstitial cells of Cajal in the deep muscular plexus of the small intestine. NK1 receptor-expressing neurons had Dogiel type I morphology and many of them were β-nicotinamide adenine phosphate dinucleotide-diaphorase-positive, indicating they are inhibitory neurons. In conclusion, in the guinea-pig small intestine, NK1 receptor stimulation evokes a myogenic excitatory motor response and a neurogenic inhibitory motor response that involves, at least in part, a nitrinergic pathway.