Aim: In the present study we examined whether histamine H4 receptors (H4Rs) have a role in gastric ulcerogenesis using a mouse model of gastric damage. Methods: The H4R antagonist JNJ7777120 and the H4R agonists VUF8430 and VUF10460 were investigated in fasted CD-1 mice against the ulcerogenic effect induced by co-administration of indomethacin (IND, 30 mg/kg s.c.) and bethanechol (BET, 5 mg/kg i.p.). Both macroscopic and histologic lesions were examined. Strain-related differences were investigated by testing JNJ7777120 also in NMRI, BALB/c and C57BL/6J mice. Results: Neither JNJ7777120 nor the H4R agonists displayed effects in the normal stomach at any dose tested (10 and 30 mg/kg s.c.). As expected, IND+BET provoked several lesions in the fundic mucosa, which were significantly reduced by JNJ7777120 (10 and 30 mg/kg s.c.). The gastroprotective effect of JNJ7777120 (10 and 30 mg/kg s.c.) was observed in CD-1, NMRI and BALB/c, but not in C57BL/6J, mice. In CD-1 mice, the H4R agonists VUF8430 and VUF10460 (both at 10 and 30 mg/kg s.c.) did not modify the damage induced by IND+BET, however VUF8430 (10 mg/kg s.c.) prevented the gastroprotection induced by JNJ7777120 (10 mg/kg s.c.). Conclusions: Data obtained with selective ligands suggest that the H4R may have a role in mouse gastric ulcerogenesis. If confirmed in humans, these data would emphasize the potential advantage of H4R blockers as gastrosparing anti-inflammatory drugs. The lack of effects of JNJ7777120 in C57BL/6J mice has to be carefully considered in the pharmacological characterization of H4R functions and/or new selective ligands.

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