Effect of fedotozine on the cardiovascular pain reflex induced by distension of the irritated colon in the anesthetized rat.

The effect of fedotozine was evaluated in a model of colonic hypersensibility to balloon distension in anesthetized rats. Acetic acid (0.6%, intracolonically) significantly enhanced the hypotension reflex response to colonic distension (P < 0.05). At a noxious pain pressure (75 mm Hg), fedotozine ((+)-(-1R)-1-phenyl-1-[(3,4,5- trimethoxy)benzyloxymethyl]-N,N-dimethyl-n-propylamine) had no effect at 0.6 and 1 mg/kg i.v. in saline-treated rats and higher doses were required to produce antinociception (ED50 = 2.57 mg/kg i.v.). By contrast, fedotozine at 0.6 and 1 mg/kg i.v. displayed 38 and 54% antinociception (P < 0.05) respectively, in acetic acid-treated animals, leading to a decrease in its ED50 (1.15 mg/kg i.v.). Similar results were obtained with (+/-)-trans-N-methyl-N-[2-(pyrrolidinyl)-cyclohexyl]benzo[b]-thiophene- 4-acetamide (PD-117,302), a kappa-opioid receptor agonist, while the antinociceptive action of morphine and a kappa-opioid receptor agonist, trans-(+/-)-3,4-dichloro-N-methyl-N-(2-[1- pyrrolidinyl]cyclohexyl)benzenacetamide ((+/-)-U-50,488H), was identical in control and acetic acid-treated animals. Nor-binaltorphimine, a selective kappa-opioid receptor antagonist, reversed the enhanced antinociceptive activity of fedotozine and PD-117,302. It is concluded that acetic acid induces colonic hypersensibility to painful mechanical stimuli and that some but not all kappa-opioid receptor ligands can have enhanced efficacy in this pathological situation.