Differences between 5‐HT₃ receptor antagonists in modulation of visceral hypersensitivity

Abstract

Noxious colo‐rectal distension was applied in conscious rats by acute balloon inflation and the effects observed as abdominal muscle contraction with the threshold typically between 10–40 mmHg. The effects of 5‐HT3 receptor antagonists on responses to noxious colo‐rectal distension were then studied in both normal rats and those pretreated with 5‐hydroxytryptophan (5‐HTP). Granisetron and ondansetron (10 μg kg−1 and 1 mg kg−1, s.c.) had no effect on visceromotor thresholds to colo‐rectal distension in normal rats. Hypersensitivity of the colo‐rectum was achieved by systemic administration of a low dose of 5‐HTP (10 mg kg−1, s.c.) which lowered the distension pressure required to induce the visceromotor reflex; analysis of variance showed a highly significant treatment effect (F1,11 = 84.26, P<0.001). Granisetron, zatosetron, bemesetron and renzapride equi‐potently increased the threshold values at which distension evoked a visceromotor reflex after dosing with 5‐HTP, with a maximal response 3.6 to 4.2 fold above saline controls, at 10 μg kg−1, s.c. Metoclopramide (10 μg kg−1) also raised the level of distension required to elicit a response. By comparison, tropisetron caused a small, non‐significant increase in visceromotor threshold values and only at high doses (1 mg kg−1), whilst ondansetron and BRL 46470 had no signficant effects at doses up to 10 mg kg−1. The response to granisetron (10 μg kg−1, s.c.) in 5‐HTP‐treated rats was unaltered by pre‐administration of naloxone (5 mg kg−1, s.c). These results suggest that a 5‐HT3‐like receptor modulates 5‐HTP‐ evoked visceral hypersensitivity. However, the rank order of antagonist potency does not correlate with their order of potency against the classically defined 5‐HT3 receptor.

Increased 5-Hydroxytryptamine Mediates Post-Inflammatory Visceral Hypersensitivity via the 5-Hydroxytryptamine 3 Receptor in Rats

“…It has been implied that the 5-HT 3 receptor is involved also in other types of visceral pain, such as stressinduced delayed visceral hyperalgesia [22], visceral hyperalgesia associated with somatic mechanical hyperalgesia by acid injection into the gastrocnemius muscle [23], and intracolonic glycerol infusion-induced visceral hypersensitivity [24]. It is noteworthy that, in previous studies, the alleviating effect of 5-HT 3 receptor antagonists was not observed in normal/control rats [12,13,22,25]. However, the effect of some 5-HT 3 receptor antagonists is still controversial in normal rats.…”

“…However, the 5-HT 3 receptor antagonists have not been active in all models of colorectal hyperalgesia. 5-HT 3 receptor antagonists were effective in reducing the visceral hypersensitivity induced by chemicals such as 5-HTP, acetic acid, glycerol and 2,4,6-trinitrobenzene sulfonic acid (TNBS) [13,14,24,26]. In a different way granisetron did not modify the delayed rectal allodynia induced by mast cell degranulation in rats.…”

“…The rats in the 5-HTPtreated group were killed 30-45 min after administration of the 5-HTP. This time point was selected in accordance with a previous study [13]. Colonic samples for histology were fixed overnight at 4°C in 0.1 M phosphate-buffered saline (PBS) solution containing 4% paraformaldehyde and 0.2% picric acid.…”

“…5-Hydroxytryptophan (5-HTP) was purchased from Sigma-Aldrich (Sigma, USA). The reference doses of all drugs were obtained from in vivo experiments [13,20].…”

“…Among these, the 5-HT 3 receptor has been extensively explored as a potential target for treating visceral pain. However, conflicting data have been obtained when different 5-HT 3 receptor antagonists from different experimental models [12][13][14] have been used, making the role of the 5-HT 3 receptor in visceral nociception inconclusive. Moreover, it has not been studied whether the 5-HT 3 receptor participates in PI-VH, which could reflect the condition of post-infectious IBS.…”