DIFFERENCES BETWEEN 5-HT3 RECEPTOR ANTAGONISTS IN MODULATION OF VISCERAL HYPERSENSITIVITY

1 Noxious cole-rectal distension was applied in conscious rats by acut e balloon inflation and the effects observed as abdominal muscle contr action with the threshold typically between 10-40 mmHg. The effects of 5-HT3 receptor antagonists on responses to noxious cole-rectal disten sion were then studied in both normal rats and those pretreated with 5 -hydroxytryptophan (5-HTP). 2 Granisetron and ondansetron (10 mu g kg( -1) and 1 mg kg(-1), s.c.) had no effect on visceromotor thresholds to cole-rectal distension in normal rats. 3 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 t o induce the visceromotor reflex; analysis of variance showed a highly significant treatment effect (F-I,F-II = 84.26, P<0.001). 4 Granisetr on, zatosetron, bemesetron and renzapride equi-potently increased the threshold values at which distension evoked a visceromotor reflex afte r dosing with 5-HTP, with a maximal response 3.6 to 4.2 fold above sal ine controls, at 10 mu g kg(-1), s.c. Metoclopramide (10 mu g kg(-1)) also raised the level of distension required to elicit a response. By comparison, tropisetron caused a small, non-significant increase in vi sceromotor threshold values and only at high doses (1 mg kg(-1)), whil st ondansetron and BRL 46470 had no significant effects at doses up to 10 mg kg(-1). 5 The response to granisetron (10 mu g kg(-1), s.c.) in 5-HTP-treated rats was unaltered by preadministration of naloxone (5 mg kg(-1), s.c.). 6 These results suggest that a 5-HT3-like receptor m odulates 5-HTP- evoked visceral hypersensitivity. However, the rank or der of antagonist potency does not correlate with their order of poten cy against the classically defined 5-HT3 receptor.