PT - JOURNAL ARTICLE AU - Shiho Okano AU - Hideaki Nagaya AU - Yoshinori Ikeura AU - Hideaki Natsugari AU - Nobuhiro Inatomi TI - Effects of TAK-637, a Novel Neurokinin-1 Receptor Antagonist, on Colonic Function in Vivo DP - 2001 Aug 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 559--564 VI - 298 IP - 2 4099 - http://jpet.aspetjournals.org/content/298/2/559.short 4100 - http://jpet.aspetjournals.org/content/298/2/559.full SO - J Pharmacol Exp Ther2001 Aug 01; 298 AB - Substance P (SP) is an important neurotransmitter that mediates various gut functions; however, its precise pathophysiological role remains unclear. In this study, we investigated the effect of SP on colonic function and the effect of TAK-637 {(aR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g][1,7]naphthyridine-6,13-dione}, a new neurokinin-1 (NK1) receptor antagonist, on colonic responses to SP or stress in Mongolian gerbils. SP and the selective NK1 agonist [pGlu6]SP6–11significantly increased fecal pellet output. TAK-637 reduced [pGlu6]SP6–11-induced defecation, but did not significantly affect neurokinin A-, 5-hydroxytryptamine- or carbachol-stimulated defecation. Oral TAK-637 decreased restraint stress-stimulated fecal pellet output with an ID50 value of 0.33 mg/kg. Ondansetron and atropine, but not the peripheral κ-receptor agonist trimebutine, also reduced restraint stress-stimulated defecation. TAK-637 inhibited the increase in fecal pellet output stimulated by intracerebroventricular injection of corticotropin-releasing factor, but did not affect the stress-induced increase in plasma adrenocorticotropic hormone levels. Denervation of the sensory neurons with capsaicin did not affect stress-stimulated defecation. These results suggest that NK1 receptors in the enteric plexus play an important role in stress-induced changes in colonic function, and that TAK-637 may be useful in the treatment of functional bowel diseases such as irritable bowel syndrome. The American Society for Pharmacology and Experimental Therapeutics