In this study, we examined the effects of serotonin (5-HT)3 receptor antagonists (5-HT3RAs) including ramosetron, alosetron, and cilansetron on colonic nociceptive threshold in rats. Furthermore, we established a restraint stress-induced colonic hyperalgesia model in rats, and compared the inhibitory effects of 5-HT3RAs on restraint stress-induced colonic hyperalgesia and diarrhoea with those of loperamide, trimebutine, tiquizium and polycarbophil. The colonic nociceptive threshold was measured as the balloon pressure at the time the rat showed a nociceptive response during colonic distension by an intrarectally inserted balloon. Oral administration of ramosetron (3-30 microg kg(-1)), alosetron (30-300 microg kg(-1)), or cilansetron (30-300 microg kg(-1)) increased the colonic nociceptive threshold in a dose-dependent manner in non-stressed rats. Restraint stress for 1 h significantly decreased the colonic nociceptive threshold, but ramosetron (0.3-3 microg kg(-1)), alosetron (3-30 microg kg(-1)), cilansetron (3-30 microg kg(-1)) and trimebutine (100-1000 mg kg(-1)) significantly inhibited the decrease in the threshold. Loperamide (3-30 mg kg(-1)), tiquizium (100-1000 mg kg(-1)) and polycarbophil (1000 mg kg(-1)) did not affect the restraint stress-induced decrease in the colonic nociceptive threshold. All drugs tested in this study showed dose-dependent inhibition of restraint stress-induced diarrhoea in rats. These results indicate that, unlike existing antidiarrhoeal and spasmolytic agents, 5-HT3RAs have inhibitory effects on colonic nociception, and prevented restraint stress-induced both diarrhoea and hyperalgesia at almost the same doses in rats. This suggests that the 5-HT3RAs may be useful in ameliorating both colonic hyperalgesia and diarrhoea in patients with irritable bowel syndrome.

Abstract. We examined the pharmacological profile of ramosetron, a 5-HT 3 -receptor antagonist for irritable bowel syndrome with diarrhea, comparing it with those of other 5-HT 3 -receptor antagonists, alosetron and cilansetron, and the anti-diarrheal agent loperamide. Ramosetron showed high affinity for cloned human and rat 5-HT 3 receptors, with K i values of 0.091 ± 0.014 and 0.22 ± 0.051 nmol / L, respectively, while its affinities for other receptors, transporters, ion channels, and enzymes were negligible. Dissociation of ramosetron from the human 5-HT 3 receptor was extremely slow (t 1/ 2 = 560 min), while alosetron (t 1/ 2 = 180 min) and cilansetron (t 1/ 2 = 88 min) dissociated relatively rapidly. Ramosetron competitively inhibited 5-HT-induced contraction of isolated guinea-pig colon, with pA 2 values of 8.6 (8.5 -9.0). Ramosetron given orally also dose-dependently inhibited the von Bezold-Jarisch reflex in rats, with an ED 50 value of 1.2 (0.93 -1.6) µg / kg. In addition, oral ramosetron dose-dependently inhibited restraint stressinduced defecation in rats, with an ED 50 value of 0.62 (0.17 -1.2) µg/ kg. In all of these experiments, the potencies of ramosetron were greater than those of alosetron, cilansetron, or loperamide. These results indicate that ramosetron is a highly potent and selective 5-HT 3 -receptor antagonist, with beneficial effects against stress-induced abnormal defecation in rats.

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Ramosetron is a potent and selective serotonin (5-HT)(3) receptor antagonist that has been shown to affect abnormal colonic function and abdominal pain in animals. Ramosetron (0.3 to 100 microg/kg, p.o.) has been found to significantly suppress abnormal defecation induced by conditioned-fear stress (CFS), restraint stress, corticotropin releasing factor (CRF) and 5-HT in rats and mice, and these effects were more potent than those of alosetron, cilansetron or loperamide. On the other hand, ramosetron (3,000 microg/kg, p. o., once daily for 7 days) did not inhibit normal defecation in dogs while tiquizium significantly inhibited it. Ramosetron (3 to 100 microg/kg, p. o.) also significantly prevented CFS-induced acceleration of colonic transit and CRF-induced abnormal water transport in rats, respectively. Moreover, ramosetron (0.3 to 3 microg/kg, p. o.) significantly suppressed restraint stress-induced decrease in colonic pain threshold, an effect not observed with loperamide. These results indicate that ramosetron produce beneficial clinical effects on IBS symptoms.

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