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In the present study, the effects of ghrelin against the gastric damage induced by intragastric administration of 0.6 N HCl and the involvement of histamine H₃ receptors (H₃Rs) were investigated in conscious rats with selective H₃R ligands. Intraperitoneal (i.p.) injection of ghrelin (40 μg/kg) significantly reduced (43%) the gastric lesions caused by concentrated acid. The effect of ghrelin was prevented by prior administration of the ghrelin receptor antagonist [D-Lys³]-GHRP-6 (100 μg/kg i.p.) and by subcutaneous (s.c.) injection of the nonimidazole H₃R antagonist UCL2138 (30 mg/kg). The selective H₃R agonist immethridine (30 mg/kg s.c.) significantly inhibited (64.60%) the gastric lesions induced by 0.6 N HCl. The effect of immethridine was prevented by prior administration of UCL2138 (30 mg/kg s.c.), but not by [D-Lys³]-GHRP-6 (100 μg/kg i.p.). Neither [D-Lys³]-GHRP-6 nor UCL2138 modified HCl-induced gastric damage per se. These data enlarge previous studies showing protective effects of ghrelin against ulcerogenic stimuli; in addition, they clearly indicate that ghrelin-induced gastroprotection involves the release of histamine, which enhances gastric mucosal defense through the activation of histamine H₃Rs.