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.
Pharmacology Research Laboratories, Drug Discovery Research, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan. toshiyuki.funatsu@jp.astellas.com
Toshiyuki
T
Funatsu
Asako
A
Takeuchi
Takuya
T
Hirata
Yoshihiro
Y
Keto
Shinobu
S
Akuzawa
Masao
M
Sasamata
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)