Glycyrrhetinic acid prevents cutaneous scratching behavior in mice elicited by substance P or PAR-2 agonist

Although glycyrrhetinic acid (GA) has been used for the prevention of itch in chronic dermatitis, the mechanism underlying the antipruritic effects of GA is still unclear. Recently, several mediators other than histamine, such as substance P and tryptase, were found to participate in chronic itch. Here, we investigated the effect of GA on pruritus induced by various pruritic agents including histamine in mice. We also determined the level of leukotriene (LT)B4 in mouse skin injected with substance P in an effort to uncover part of the antipruritic mechanism of GA. Scratching events were counted for 10 min after intradermal injection of histamine, substance P (100 nmol per site each), protease-activated receptor-2 (PAR-2) agonistic peptide (50 nmol per site), or LTB4 (0.03 nmol per site) with or without GA (4 nmol per site) into male ICR mice. Levels of LTB4 in the skin after injection of substance P were determined by ELISA. GA did not suppress scratching behavior induced by histamine and LTB4, but markedly and dose-dependently suppressed that induced by substance P and PAR-2 agonistic peptide. LTB4 levels in skin elevated by substance P were lowered by GA. These data support the efficacy of GA in counteracting itch in chronic dermatitis because GA reduced scratching behavior induced by substance P and PAR-2 agonistic peptide. GA may exert antipruritic effects via inhibition of LTB4 production in skin.