5-HT4 receptor antagonism potentiates inhibition of intestinal allodynia by 5-HT3 receptor antagonism in conscious rats.
Acute levels of distension were applied by balloon to the colo-rectal region in conscious rats and visceromotor responses observed as abdominal muscle contraction; the threshold was typically between 10-40 mmHg. In saline-pretreated rats, the selective 5-HT3 (granisetron) and 5-HT4 (SB-207266) receptor antagonists had no effects on the visceromotor thresholds. 5-Hydroxytryptophan 10 mg/kg, subcutaneously (s.c.) decreased the distension threshold, indicating mechanical allodynia. This increased sensitivity was dose-dependently inhibited by granisetron but was unaffected by SB-207266 100 microg/kg, s.c., a dose which maximally and selectively antagonizes at 5-HT4 receptors. However, this dose of SB-207266 potentiated the inhibitory activity of submaximally-effective doses of granisetron, reducing the ED50 from 0.83 to 0.02 microg/kg, s.c., but without changing the maximum response or the bell-shaped nature of the dose-response curve for granisetron. These data suggest that 5-HT4 receptor activation enhances the ability of 5-HT3 receptor activation to induce intestinal allodynia.
Smith
M I
MI
SmithKline Beecham Pharmaceuticals, Harlow, Essex, UK.
Banner
S E
SE
Sanger
G J
GJ
D000818:Animals; D003106:Colon / Q000187:drug effects / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D017829:Granisetron / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D010146:Pain / Q000503:physiopathology*; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000502:physiology*; D044406:Receptors, Serotonin, 5-HT3; D044422:Receptors, Serotonin, 5-HT4; D012007:Rectum / Q000187:drug effects / Q000502:physiology*; D012702:Serotonin Antagonists / Q000494:pharmacology*
D017829:Granisetron; D007211:Indoles; D010880:Piperidines; D011985:Receptors, Serotonin; D044406:Receptors, Serotonin, 5-HT3; D044422:Receptors, Serotonin, 5-HT4; D012702:Serotonin Antagonists; C096919:SB 207266