Involvement of leukotriene B4 in substance P-induced itch-associated response in mice

Intradermal injection of substance P elicits an itch sensation in human subjects and an itch-associated response in mice. The substance P-induced itch-associated response in mice is not inhibited by antihistamine. Therefore, the mechanisms of substance P-induced itch-associated response are unclear. In this study, we demonstrated one of the mechanisms. Substance P induces an arachidonate cascade to produce prostaglandins and leukotriene. In this study we considered whether arachidonate metabolites are involved in the substance P-induced itch-associated response. A phospholipase A(2) inhibitor arachidoryl-trifluoromethyl ketone inhibited the substance P-induced itch-associated response in mice. Pretreatment with the glucocorticoids betamethasone and dexamethasone also produced inhibition of the substance P-induced itch-associated response in mice as well as humans. The 5-lipoxygenase inhibitor zileuton, but not the cyclooxygenase inhibitors indomethacin and diclofenac, suppressed substance P-induced itch-associated response. The leukotriene B-4 receptor antagonist 5-[2-(2-carboxyethyl)-3-{6-(4-methoxyphenyl)-5E-hexenyl}oxyphenoxy]valeric acid produced inhibition, whereas pranlukast (leukotriene C-4/D-4/E-4 receptor antagonist) and 5(Z)-7-[1S,2S, 3S,5R-3-(traps-b-styren)sulfonamido-6,6-dimethylbicyclo(3,1,1)hept-2-yl]-5-heptenoic acid (EP, receptor antagonist) were without effect. Furthermore, when the production of leukotriene B-4 and prostaglandin E-2 was measured in skin injected with substance P and in mouse keratinocytes applied with substance P, the level of both products increased. As leukotriene B-4, but not prostaglandin E-2, also induces the itch-associated response in mice, these results suggest that leukotriene B-4 and keratinocytes, cutaneous cells which produced leukotriene B-4, play an important role in substance P-induced itch-scratch response in mice. Leukotriene B4 receptor antagonist and 5-lipoxygenase inhibitor may be novel antipruritic drugs.