Vol. 300, Issue 3, 925-931, March 2002

Effects of Tachykinin NK₁ Receptor Antagonists on the Viscerosensory Response Caused by Colorectal Distention in Rabbits

Shiho Okano, Yoshinori Ikeura and Nobuhiro Inatomi

Pharmaceutical Research Division, Takeda Chemical Industries, Ltd., Osaka, Japan

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.