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Background and Aim: Gastric hypersensitivity to mechanical distension has been observed in functional dyspepsia, but no drug is available that specifically acts on gastric afferent pathways to decrease gastric nociception. The aim of this study was to assess the effect of fedotozine, a synthetic ligand for peripheral kappa receptors, on human gastric sensitivity., Methods: Twenty-seven healthy volunteers were randomized to receive either fedotozine (30 mg t.d.s.) or a placebo, for 7 days. On day 7, the effects of fedotozine were tested on discomfort threshold and gastric compliance during graded isobaric and isovolumic distensions. In 16 of these subjects, the effect of this drug was tested on somatic sensitivity. In 10 other healthy volunteers the effect of fedotozine on gastric distension-induced inhibition of the RIII reflex, a process closely related to visceral sensitivity, was also studied., Results: During isobaric distensions, the discomfort threshold was significantly higher in subjects on fedotozine than in those on placebo (14.4 +/- 0.92 vs. 12.0 +/- 1.13 mmHg; P = 0.04). Compared to placebo, fedotozine did not modify gastric compliance and somatic sensitivity. Fedotozine also reduced the inhibition of the RIII reflex induced by gastric distension., Conclusion: Fedotozine decreases gastric sensitivity to distension by exerting specific action on gastric afferent pathways.