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Abstract: Ghrelin is an orexigenic peptide present in the stomach with gastroprokinetic properties. Previous in vivo studies have shown that the ghrelin receptor antagonist, D-Lys3-GHRP-6, reduced food intake and delayed gastric emptying in rodents but these effects are at variance with the normal phenotype of the ghrelin knockout mice. To verify the specificity of the effects observed with D-Lys3-GHRP-6 this study aimed to investigate the pharmacology of D-Lys3-GHRP-6 in vitro. Rat fundic strips were suspended in a tissue bath and the contraction of strips to 10−5 M of ghrelin, GHRP-6 or D-Lys3-GHRP-6 was measured isometrically in the absence and presence of blockers. Neither ghrelin, nor GHRP-6, induced significant contractions in the absence of electrical field stimulation thereby excluding the presence of ghrelin receptors on smooth muscle cells. In contrast D-Lys3-GHRP-6, induced a pronounced biphasic contraction of 13.9±1.8% and 40.5±3.2% relative to the response to 60 mM KCl. The contraction was blocked by the 5-HT1,2 receptor antagonist methysergide and was markedly reduced by the 5-HT2B receptor antagonist, yohimbine, which also profoundly affected 5-HT induced contractions in fundic strips. The existence of 5-HT2B receptors in the fundus was confirmed by use of the 5-HT2B receptor agonist, BW 723C86. In contrast to ghrelin and GHRP-6, the ghrelin receptor antagonist, D-Lys3-GHRP-6, induced pronounced smooth muscle contractions in the rat fundus by interacting with 5-HT2B receptors. This may question the role of endogenous ghrelin in the effects observed with D-Lys3-GHRP-6 on food intake and gastric emptying in vivo. [Copyright &y& Elsevier]