Effects of serotonin 5-HT3 receptor antagonists on stress-induced colonic hyperalgesia and diarrhoea in rats: a comparative study with opioid receptor agonists, a muscarinic receptor antagonist and a synthetic polymer.
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.
Hirata
T
T
Applied Pharmacology Research Laboratories, Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Ibaraki, Japan. takuya.hirata@jp.astellas.com
Keto
Y
Y
Nakata
M
M
Takeuchi
A
A
Funatsu
T
T
Akuzawa
S
S
Sasamata
M
M
Miyata
K
K
D000701:Analgesics, Opioid / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D003106:Colon / Q000187:drug effects / Q000378:metabolism; D003967:Diarrhea / Q000188:drug therapy* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006930:Hyperalgesia / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D008297:Male; D018727:Muscarinic Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D011108:Polymers / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D011957:Receptors, Opioid / Q000819:agonists / Q000502:physiology; D044406:Receptors, Serotonin, 5-HT3 / Q000378:metabolism; D058831:Serotonin 5-HT3 Receptor Antagonists; D012702:Serotonin Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D013315:Stress, Psychological / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism
D000701:Analgesics, Opioid; D018727:Muscarinic Antagonists; D011108:Polymers; D011957:Receptors, Opioid; D044406:Receptors, Serotonin, 5-HT3; D058831:Serotonin 5-HT3 Receptor Antagonists; D012702:Serotonin Antagonists