Effect of ramosetron on conditioned emotional stress-induced colonic dysfunction as a model of irritable bowel syndrome in rats.
The aim of this study was to establish a pathophysiologic model of irritable bowel syndrome, and then to evaluate the pharmaceutical efficacy of ramosetron, a potent serotonin 3 (5-HT(3)) receptor antagonist, and other anti-irritable bowel syndrome agents in this model. Rats stressed by a conditioned stress procedure exhibited marked prolongation of freezing time, an index of fear level, and an increase in the frequency of defecation (P<0.01). A corticotropin-releasing factor (CRF) antagonist, alpha-helical CRF, inhibited both defecation and freezing behavior, while the antidiarrheal loperamide inhibited defecation only. The 5-HT(3) receptor antagonists ramosetron, cilansetron and alosetron also inhibited defecation (ED(50) values: 0.012, 0.094, 0.078 mg/kg p.o., respectively) without affecting freezing behavior. Ramosetron showed longer-lasting effect on defecation than cilansetron. Stress also resulted in increases in both proximal and distal colonic transit rates. Ramosetron and other 5-HT(3) receptor antagonists at doses inhibiting stress-induced defecation also ameliorated both stress-stimulated colonic transit rates. These results suggest that ramosetron, as well as agents used for the treatment of irritable bowel syndrome with diarrhea, has beneficial effects against emotional stress-induced colonic dysfunction. Furthermore, this emotional stress model may be useful in evaluation of drugs to treat irritable bowel syndrome presenting with diarrhea.
Funatsu
Toshiyuki
T
Pharmacology Research Laboratories, Drug Discovery Research, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan. toshiyuki.funatsu@jp.astellas.com
Takeuchi
Asako
A
Hirata
Takuya
T
Keto
Yoshihiro
Y
Akuzawa
Shinobu
S
Sasamata
Masao
M
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001562:Benzimidazoles / Q000494:pharmacology*; D002227:Carbazoles / Q000494:pharmacology; D002243:Carbolines / Q000494:pharmacology; D003106:Colon / Q000187:drug effects / Q000503:physiopathology; D003109:Colonic Diseases, Functional / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D003213:Conditioning, Psychological / Q000187:drug effects; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology; D003672:Defecation / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005239:Fear / Q000187:drug effects / Q000523:psychology; D005772:Gastrointestinal Transit / Q000187:drug effects; D007103:Immobilization / Q000523:psychology; D043183:Irritable Bowel Syndrome / Q000503:physiopathology / Q000517:prevention & control* / Q000523:psychology; D008139:Loperamide / Q000494:pharmacology; D008297:Male; D010446:Peptide Fragments / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044406:Receptors, Serotonin, 5-HT3 / Q000502:physiology; D058831:Serotonin 5-HT3 Receptor Antagonists; D012702:Serotonin Antagonists / Q000494:pharmacology; D013315:Stress, Psychological / Q000150:complications / Q000503:physiopathology*; D013997:Time Factors; D016896:Treatment Outcome
D001562:Benzimidazoles; D002227:Carbazoles; D002243:Carbolines; D010446:Peptide Fragments; D011725:Pyridines; D044406:Receptors, Serotonin, 5-HT3; D058831:Serotonin 5-HT3 Receptor Antagonists; D012702:Serotonin Antagonists; C090840:alosetron; C084473:cilansetron; D008139:Loperamide; C071315:ramosetron; D003346:Corticotropin-Releasing Hormone; C045089:corticotropin releasing hormone (9-41)