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

Abstract

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.

Involvement of 5-HT3 and 5-HT4 Receptors in the Regulation of Circadian Clock Gene Expression in Mouse Small Intestine

“…Stress is known to increase 5-HT release and result in colonic hypersensitivity in animals and humans. This symptom is alleviated by various 5-HT 3 receptor antagonists (23,26). Disturbances of circadian rhythms such as shift work worsened IBS (18 -20).…”

Role of Corticotropin-releasing Factor in Gastrointestinal Permeability

“…Convergent evidences from studies in animal models indicate that both water and ion secretions increase in the intestinal tract in response to acute and chronic stress 24,46 and in response to peripheral administration of CRF 47 whereas selective CRF 1 receptor agonists prevent this response to stress. 48,49 Increased baseline short-circuit current (Isc), indicative of enhanced anion secretion, was found in the jejunum of WistarKyoto rats submitted to restraint stress or cold restraint stress when compared to non-stressed rats.…”

A Phase II Trial of the Novel Serotonin Type 3 Receptor Antagonist Ramosetron in Japanese Male and Female Patients with Diarrhea-Predominant Irritable Bowel Syndrome

“…In the intestinal nerves, 5-HT acts on the 5-HT 3 receptors on parasympathetic ganglia to cause the contraction of intestinal smooth muscle and an increase in intestinal secretion by stimulating acetylcholine release from nerve terminals. 5-HT 3 receptor antagonists have been reported to inhibit the accelerated colonic transit, abnormal colonic water transport, defecation abnormality (increased defecation and diarrhea), and the lowered colonic perceptual threshold by corticotropin-releasing hormone (CRH) or stress in animals [1,2,3], which suggested the involvement of 5-HT 3 in the pathophysiology of irritable bowel syndrome (IBS). Accordingly, 5-HT 3 receptor antagonists are expected to improve stress-induced motility dysfunction in the lower gastrointestinal tract, including IBS in clinical practice.…”