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

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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−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.