title: Depletion of substance P, a mechanism for inhibition of mouse scratching behavior by tacrolimus.
abstract: Itching is the most important problem in atopic dermatitis and tacrolimus has been suggested to attenuate the itching by topical application. However, the anti-itch mechanism of tacrolimus has not been well elucidated. In the present study, an allergic dermatitis accompanied by frequent scratching behaviors was induced by repeated paintings with 2,4-dinitrofluorobenzene (DNFB) acetone solution onto the mouse ear and the effects of tacrolimus and dexamethasone on the dermatitis and associated scratching behavior were comparatively examined. Repeated DNFB paintings caused a typical dermatitis accompanied by elevated serum immunoglobulin E (IgE) and frequent scratching behaviors. Both tacrolimus and dexamethasone given topically for 10 days before the final challenge significantly inhibited the ear swelling and reduced the expression of interferon-gamma mRNA. Dexamethasone inhibited the accumulation of eosinophils completely, although tacrolimus did not. Both drugs did not affect the elevation of serum IgE levels. Tacrolimus significantly inhibited the scratching behavior, whereas dexamethasone failed to affect it. Repeated DNFB challenge depleted substance P in the dermis. Treatment with tacrolimus before the final challenge completely inhibited the recovery of substance P content, whereas dexamethasone facilitated the recovery. DNFB-induced ear swelling and scratching behavior were significantly inhibited by FK888, a tachykinin NK(1) receptor antagonist. Therefore, substance P seems to participate in the induction of ear swelling and scratching behavior upon final challenge with DNFB, and depletion of substance P by tacrolimus in the dermis contributes to its inhibition of ear swelling and scratching behavior at least in part.
authors.affiliation: Laboratory of Pharmacology, Department of Bioactive Molecules, Gifu Pharmaceutical University, 5-6-1 Mitahorahigashi, Gifu 502-8585, Japan. inagakin@gifu-pu.ac.jp
authors.forename: Naoki
authors.initials: N
authors.lastname: Inagaki
authors.forename: Noriko
authors.initials: N
authors.lastname: Shiraishi
authors.forename: Katsuhiro
authors.initials: K
authors.lastname: Igeta
authors.forename: Masafumi
authors.initials: M
authors.lastname: Nagao
authors.forename: John Fan
authors.initials: JF
authors.lastname: Kim
authors.forename: Takao
authors.initials: T
authors.lastname: Chikumoto
authors.forename: Tomokazu
authors.initials: T
authors.lastname: Itoh
authors.forename: Hideo
authors.initials: H
authors.lastname: Katoh
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tanaka
authors.forename: Hiroichi
authors.initials: H
authors.lastname: Nagai
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D003876:Dermatitis, Atopic / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D003907:Dexamethasone / Q000494:pharmacology; D004423:Ear / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011537:Pruritus / Q000188:drug therapy* / Q000378:metabolism* / Q000503:physiopathology; D013373:Substance P / Q000172:deficiency* / Q000378:metabolism*; D016559:Tacrolimus / Q000494:pharmacology* / Q000627:therapeutic use*
chemical_list: D013373:Substance P; D003907:Dexamethasone; D016559:Tacrolimus