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

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 NK 1 receptors in the visceral pain response (abdominal muscle contraction) caused by colorectal distention in rabbits previously subjected to colonic irritation, using the selective tachykinin NK 1 receptor antagonists TAK-637 [(aR,9R)-7-[3,5-Bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-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 NK 1 antagonist, (Ϯ)-CP-99,994, also reduced the number of abdominal contractions. In contrast, the enantiomer of TAK-637 (which has very weak tachykinin NK 1 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 NK 1 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 (Ϯ)-CP-99,994 markedly reduced the number of abdominal contractions. These results suggest that tachykinin NK 1 receptors play an important role in mediating visceral pain and that TAK-637 inhibits the viscerosensory response to colorectal distention by antagonizing tachykinin NK 1 receptors, mainly in the spinal cord. They also suggest that TAK-637 may be useful in treating functional bowel disorders such as IBS.

Establishment and Validation of a Rabbit Model for In Vivo Pharmacodynamic Screening of Tachykinin NK2 Antagonists

“…For this purpose, we used a rabbit CRD model based on the pharmacologically validated model reported by Okano et al (10). Using this disease model, a series of compounds were evaluated and were found to inhibit the VMR to CRD in a dose-dependent manner.…”

“…Surgery was performed according to the previously reported procedure (10). Under ketamine/xylazine anesthesia, the lower left abdominal musculature was exposed.…”

Effects of TAK-480, a Novel Tachykinin NK2^|^ndash;Receptor Antagonist, on Visceral Hypersensitivity in Rabbits and Ricinoleic Acid^|^ndash;Induced Defecation in Guinea Pigs

“…As described previously (19), all surgical procedures were performed under pentobarbital sodium anesthesia. The lower left abdominal musculature (abdominal external oblique muscle) was exposed, and a force transducer was attached for monitoring abdominal muscle contractions, that is, the visceromotor response (VMR) to CRD.…”

“…Our study clearly demonstrated that TAK-480 possesses a unique property showing species-related differences in the binding affinity for the NK 2 receptor (higher affinity for human, rabbit, and guinea pig in nM order and lower affinity for rat in μM order) in accordance with heterogeneity of the receptor (18). Therefore, we investigated the efficacy of TAK-480 in non-rodent animal models partially-modified from original ones: a rabbit model of zymosan-induced visceral hypersensitivity and a guinea-pig model of ricinoleic acid-induced defecation, which partially mimic common characteristics of IBS (19,20). In addition, we examined NK 2 -receptor antagonism in isolated human colon specimens to further predict the clinical efficacy of TAK-480.…”

Effects of Mosapride Citrate, a 5-HT4–Receptor Agonist, on Gastric Distension–Induced Visceromotor Response in Conscious Rats

“…A flexible latex balloon catheter was surgically placed into the stomach though a small incision at the forestomach. A force transducer (F-08IS; StarMedical, Tokyo) was then sutured to the abdominal external oblique muscle as previously reported (14,16) to measure the number of abdominal contractions as an indicator of visceral pain sensation.…”