Involvement of leukotriene B(4) 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 arachidoryltrifluoromethyl ketone inhibited the substance P-induced itch-associated response in mice. Pre treatment 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-(trans-b-styren)sulfonamido-6,6-dimethylbi cyclo(3,1,1)hept-2-yl]-5-heptenoic acid (EP(1) 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 B(4) receptor antagonist and 5-lipoxygenase inhibitor may be novel antipruritic drugs.
Andoh
T
T
Department of Applied Pharmacology, Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University, Toyama, Japan.
Katsube
N
N
Maruyama
M
M
Kuraishi
Y
Y
D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D016718:Arachidonic Acid / Q000378:metabolism; D001095:Arachidonic Acids / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005938:Glucocorticoids / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D015603:Keratinocytes / Q000276:immunology* / Q000378:metabolism; D007975:Leukotriene B4 / Q000276:immunology* / Q000378:metabolism; D016859:Lipoxygenase Inhibitors; D008297:Male; D008407:Mast Cells; D051379:Mice; D008813:Mice, Inbred ICR; D008817:Mice, Mutant Strains; D010666:Phenylpropionates / Q000494:pharmacology; D010741:Phospholipases A / Q000037:antagonists & inhibitors / Q000378:metabolism; D011537:Pruritus / Q000139:chemically induced / Q000276:immunology*; D018102:Receptors, Leukotriene B4 / Q000037:antagonists & inhibitors / Q000378:metabolism; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D013373:Substance P / Q000494:pharmacology*
D001095:Arachidonic Acids; D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D016859:Lipoxygenase Inhibitors; D010666:Phenylpropionates; D018102:Receptors, Leukotriene B4; D018040:Receptors, Neurokinin-1; C081565:arachidonyltrifluoromethane; C067523:ONO-LB 457; D007975:Leukotriene B4; D016718:Arachidonic Acid; D013373:Substance P; D003907:Dexamethasone; D001094:Arachidonate 5-Lipoxygenase; D010741:Phospholipases A; D015232:Dinoprostone; D007213:Indomethacin