FEDOTOZINE BLOCKS HYPERSENSITIVE VISCERAL PAIN IN CONSCIOUS RATS - ACTION AT PERIPHERAL KAPPA-OPIOID RECEPTORS

The effect of fedotozine on visceral hypersensitivity was evaluated in conscious rats. One hour after colonic irritation (0.6% acetic acid i ntracolonically), a 30 mmHg colonic distension was applied for 10 min. Irritation increased the number of abdominal contractions induced by colonic distension (23.4 +/- 4.1 versus 4.8 +/- 1.4 in saline-treated rats, P < 0.001). Facilitation of colonic pain was reversed in a dose- dependent manner by fedotozine -1-phenyl-1-[(3,4,5-trimethoxy)benzylox ymethyl]-N, N-dimethyl-n-propylamine), (+/-)-U-50,488H l-N-(2-[1-pyrro lidinyl]cyclohexyl)benzeneacetamide and morphine (respective ED50 valu es 0.67, 0.51 and 0.23 mg/kg s.c.). The kappa-opioid receptor antagoni st, nor-binaltorphimine, abolished the effects of fedotozine and (+/-) -U-50,488H but not those of morphine. Low doses of naloxone (30 mu g/k g s.c.) blocked the effect of morphine but not of fedotozine or (+/-)- U-50,488H. After intracerebroventricular administration, morphine was very potent (ED50 1.7 mu g/rat), (+/-)-U-50,488H poorly active (58% of antinociception at 300 mu g/rat) and fedotozine inactive up to 300 mu g/rat. These results show that fedotozine blocks hypersensitive visce ral pain by acting on peripheral kappa-opioid receptors in animals. (C ) 1997 Elsevier Science B.V.