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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

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

Shiho Okano, Yoshinori Ikeura and Nobuhiro Inatomi
Journal of Pharmacology and Experimental Therapeutics March 2002, 300 (3) 925-931; DOI: https://doi.org/10.1124/jpet.300.3.925
Shiho Okano
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Yoshinori Ikeura
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Nobuhiro Inatomi
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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.

Footnotes

  • Abbreviations:
    IBS
    irritable bowel syndrome
    NK
    neurokinin
    SP
    substance P
    CNS
    central nervous system
    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
    M-I
    metabolite I
    (±)-CP-99,994
    (±)-(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine
    L-733,060
    ((2S,3S)-3-((3,5-bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidine
    • Received August 2, 2001.
    • Accepted October 30, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 300 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 300, Issue 3
1 Mar 2002
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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

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

Shiho Okano, Yoshinori Ikeura and Nobuhiro Inatomi
Journal of Pharmacology and Experimental Therapeutics March 1, 2002, 300 (3) 925-931; DOI: https://doi.org/10.1124/jpet.300.3.925

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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

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

Shiho Okano, Yoshinori Ikeura and Nobuhiro Inatomi
Journal of Pharmacology and Experimental Therapeutics March 1, 2002, 300 (3) 925-931; DOI: https://doi.org/10.1124/jpet.300.3.925
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