Potent pruritogenic action of tryptase mediated by PAR-2 receptor and its involvement in anti-pruritic effect of nafamostat mesilate in mice.
The pruritogenic potency of tryptase and its involvement in anti-pruritic effect of intravenous nafamostat mesilate (NFM) were studied in mice. An intradermal injection of tryptase (0.05-1 ng/site) elicited scratching in ICR mice, while chymase was without effects at doses of 0.05-50 ng/site. The dose-response curve of tryptase action was bell-shaped and the effect peaked at 0.1 ng/site (approximately 0.7 fmol/site). NFM (10 mg/kg) inhibited scratching induced by tryptase but not by histamine and serotonin. NFM (1-10 mg/kg) produced the dose-dependent inhibition of scratching induced by intradermal compound 48/80 (10 microg/site). The inhibition by NFM (10 mg/kg) was abolished in mast cell-deficient (WBB6F1 W/W(V)) mice, but not in wild-type (WBB6F1 +/+) mice. NFM (10 mg/kg) suppressed tryptase activity in the mouse skin. Proteinase-activated receptor-2 (PAR-2) neutralizing antibody (0.1 and 1 microg/site) and the PAR-2 antagonist FSLLRY (10 and 100 microg/site) inhibited scratching induced by tryptase (0.1 ng/site) and compound 48/80 (10 microg/site). These results suggest that mast cell tryptase elicits itch through PAR-2 receptor and that NFM inhibits itch-associated responses mainly through the inhibition of mast cell tryptase.
Ui
Haruna
H
Department of Applied Pharmacology, Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical Sciences, Japan.
Andoh
Tsugunobu
T
Lee
Jung-Bum
JB
Nojima
Hiroshi
H
Kuraishi
Yasushi
Y
D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D000982:Antipruritics / Q000494:pharmacology*; D001550:Benzamidines; D004305:Dose-Response Relationship, Drug; D005119:Extravasation of Diagnostic and Therapeutic Materials / Q000209:etiology / Q000517:prevention & control; D006146:Guanidines / Q000494:pharmacology*; D006632:Histamine / Q000008:administration & dosage / Q000633:toxicity; D006634:Histamine H1 Antagonists / Q000494:pharmacology; D007271:Injections, Intradermal; D007976:Leupeptins / Q000008:administration & dosage / Q000633:toxicity; D008297:Male; D008407:Mast Cells / Q000502:physiology; D051379:Mice; D008813:Mice, Inbred ICR; D008817:Mice, Mutant Strains; D009842:Oligopeptides / Q000276:immunology / Q000494:pharmacology; D011537:Pruritus / Q000139:chemically induced / Q000276:immunology / Q000517:prevention & control*; D044464:Receptor, PAR-2 / Q000276:immunology / Q000502:physiology*; D012697:Serine Endopeptidases / Q000008:administration & dosage / Q000276:immunology / Q000633:toxicity; D012701:Serotonin / Q000008:administration & dosage / Q000633:toxicity; D012867:Skin / Q000187:drug effects / Q000201:enzymology; D016593:Terfenadine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D013997:Time Factors; D053802:Tryptases; D003189:p-Methoxy-N-methylphenethylamine / Q000008:administration & dosage / Q000633:toxicity
D000906:Antibodies; D000982:Antipruritics; D001550:Benzamidines; D006146:Guanidines; C508716:H-Phe-Ser-Leu-Leu-Arg-Tyr-NH2; D006634:Histamine H1 Antagonists; D007976:Leupeptins; D009842:Oligopeptides; D044464:Receptor, PAR-2; C509190:Tpsb2 protein, mouse; D012701:Serotonin; D003189:p-Methoxy-N-methylphenethylamine; D016593:Terfenadine; D006632:Histamine; D012697:Serine Endopeptidases; C509222:Tpsab1 protein, mouse; D053802:Tryptases; C032854:leupeptin; C032855:nafamostat