Irritable bowel syndrome (IBS) is a common disorder mainly characterized by altered bowel habits and
visceral pain. In this study, we investigated the role of
tachykinin NK1 receptors in the
visceral pain response (abdominal muscle contraction) caused by colorectal distention in rabbits previously subjected to colonic irritation, using the selective
tachykinin NK1 receptor antagonists
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] and (+/-)-
CP-99,994 (+/-)-(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine. Intracolorectal administration of 0.8%
acetic acid solution enhanced the nociceptive response to colorectal distention, producing a significant increase in the number of abdominal muscle contractions. Under these conditions, intraduodenal
TAK-637 (0.1-3 mg/kg) dose dependently decreased the number of distention-induced abdominal contractions, and a significant inhibitory effect was observed with doses of 0.3 to 3 mg/kg. Another
tachykinin NK1 antagonist, (+/-)-
CP-99,994, also reduced the number of abdominal contractions. In contrast, the enantiomer of
TAK-637 (which has very weak
tachykinin NK1 receptor antagonistic activity),
trimebutine maleate,
ondansetron, and
atropine sulfate did not inhibit the abdominal response. The main metabolite of
TAK-637, which has more potent
tachykinin NK1 receptor antagonistic activity but permeates the central nervous system less well than
TAK-637, produced less inhibition of the viscerosensory response. When given intrathecally,
TAK-637 and (+/-)-
CP-99,994 markedly reduced the number of abdominal contractions. These results suggest that
tachykinin NK1 receptors play an important role in mediating
visceral pain and that
TAK-637 inhibits the viscerosensory response to colorectal distention by antagonizing
tachykinin NK1 receptors, mainly in the spinal cord. They also suggest that
TAK-637 may be useful in treating functional bowel disorders such as IBS.