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Published on: February 13, 2018
A selective, high affinity 5-HT 2B receptor antagonist inhibits visceral hypersensitivity in rats
K Ohashi-Doi1, D Himaki, K Nagao
1Discovery Research, Nagoya Laboratories, Pfizer Global Research and Development, Aichi, Japan. kdoi@unimelb.edu.au
Background:
RS-127445 is a selective, high affinity 5-HT(2B)receptor antagonist. We investigated whether 5-HT(2B)receptor antagonists can reduce colonic visceral hypersensitivity caused by restraint stress or by proximal colonic inflammation.
Methods:
Visceral hypersensitivity was induced in rats by either restraint stress or injection of 2, 4, 6-trinitrobenzene sulfonic acid (TNBS) into the proximal colon. Restraint stress produced a significant increase in numbers of abdominal contractions evoked by colorectal distension (CRD), measured as a quantitative index of visceral nociception in rats. Seven days after TNBS injection, the pain threshold to CRD at the non-inflamed distal colon, that was determined as the minimum pressure required to evoke abdominal cramp, was significantly decreased. The effect of RS-127445 on visceral hypersensitivity was assessed in either naïve or TNBS-treated rats.
Key Results:
Oral administration of a selective, high affinity 5-HT(2B)receptor antagonist, RS-127445, significantly inhibited visceral hypersensitivity provoked by restraint stress (35 to 74% inhibition at 1 to 10 mg kg(-1)). Oral RS-127445 produced a significant suppression of TNBS-induced visceral hypersensitivity (15 to 62% inhibition at 3 to 30 mg kg(-1)), although it was without significant effect on the visceral nociceptive threshold of naïve rats. RS-127445 (1 to 30 mg kg(-1), p.o.) also dose-dependently reduced the restraint stress-induced defecation in naïve and TNBS-treated rats.
Conclusions & Inferences:
These results suggest that 5-HT(2B)receptors are involved in signaling from the colon in rats in which there is visceral hypersensitivity and that a selective 5-HT(2B)receptor antagonist could have therapeutic potential for the treatment of gut disorders characterized by visceral hypersensitivity.
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