Differences between 5-HT3 receptor antagonists in modulation of visceral hypersensitivity.
1. 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). 2. Granisetron and ondansetron (10 micrograms kg-1 and 1 mg kg-1, s.c.) had no effect on visceromotor thresholds to colo-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 to induce the visceromotor reflex; analysis of variance showed a highly significant treatment effect (F1,11 = 84.26, P < 0.001). 4. 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 micrograms kg-1, s.c. Metoclopramide (10 micrograms 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 significant effects at doses up to 10 mg kg-1. 5. The response to granisetron (10 micrograms kg-1, s.c.) in 5-HTP-treated rats was unaltered by pre-administration of naloxone (5 mg kg-1, s.c.). 6. 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.
Banner
S E
SE
SmithKline Beecham Pharmaceuticals, Harlow, Essex.
Sanger
G J
GJ
D006916:5-Hydroxytryptophan / Q000494:pharmacology; D000818:Animals; D003106:Colon / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D003109:Colonic Diseases, Functional / Q000503:physiopathology; D006967:Hypersensitivity / Q000503:physiopathology*; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D009270:Naloxone / Q000494:pharmacology; D010812:Physical Stimulation; D011312:Pressure; D051381:Rats; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology*
D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D009270:Naloxone; D006916:5-Hydroxytryptophan