A selective, high affinity 5-HT 2B receptor antagonist inhibits visceral hypersensitivity in rats.
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.


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
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.
Ohashi-Doi
K
K
Discovery Research, Nagoya Laboratories, Pfizer Global Research and Development, Aichi, Japan. kdoi@unimelb.edu.au
Himaki
D
D
Nagao
K
K
Kawai
M
M
Gale
J D
JD
Furness
J B
JB
Kurebayashi
Y
Y
D000704:Analysis of Variance; D000818:Animals; D003106:Colon / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D006967:Hypersensitivity / Q000188:drug therapy* / Q000503:physiopathology; D007211:Indoles / Q000494:pharmacology; D007249:Inflammation / Q000473:pathology / Q000503:physiopathology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects* / Q000502:physiology; D009130:Muscle, Smooth / Q000187:drug effects* / Q000503:physiopathology; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044403:Receptor, Serotonin, 5-HT2B / Q000502:physiology*; D012149:Restraint, Physical; D058830:Serotonin 5-HT2 Receptor Antagonists; D018709:Statistics, Nonparametric; D013312:Stress, Physiological / Q000502:physiology; D014302:Trinitrobenzenesulfonic Acid / Q000633:toxicity; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology
D007211:Indoles; C092756:N-(1-methyl-5-indolyl)-N'-(3-methyl-5-isothiazolyl)urea; D011743:Pyrimidines; D044403:Receptor, Serotonin, 5-HT2B; D058830:Serotonin 5-HT2 Receptor Antagonists; C121466:2-amino-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine; D014302:Trinitrobenzenesulfonic Acid; D014508:Urea