Abstract

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 NK₁receptors 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.