title: A mouse model of peripheral postischemic dysesthesia: involvement of reperfusion-induced oxidative stress and TRPA1 channel.
abstract: Peripheral postischemic dysesthesia was examined behaviorally in mice and we investigated the underlying molecular mechanism with a focus on oxidative stress. Hind-paw ischemia was induced by tight compression of the ankle with a rubber band, and reperfusion was achieved by cutting the rubber tourniquet. We found that reperfusion after ischemia markedly provoked licking of the reperfused hind paw, which was significantly inhibited by systemic administration of the antioxidant N-acetyl-l-cysteine and the transient receptor potential (TRP) A1 channel blocker HC-030031 [2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)-N-(4-isopropylphenyl)acetamide]. Postischemic licking was also significantly inhibited by an intraplantar injection of another antioxidant, phenyl-N-tert-butylnitrone. The TRPV1 channel blocker BCTC [N-(4-tert-butylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2H)-carboxamide] did not inhibit postischemic licking. An intraplantar injection of hydrogen peroxide elicited hind-paw licking, which was inhibited by N-acetyl-l-cysteine, phenyl-N-tert-butylnitrone, and HC-030031. Postischemic licking was not affected by chemical depletion of sensory C-fibers, but it was inhibited by morphine, which has been shown to inhibit the C- and Aδ-fiber-evoked responses of dorsal horn neurons. Interestingly, postischemic licking was not inhibited by gabapentin and pregabalin, which have been shown to inhibit the C-fiber- but not Aδ-fiber-evoked response. The present results suggest that ischemia-reperfusion induces oxidative stress, which activates TRPA1 channels to provoke postischemic licking. It has been suggested that this behavior is mediated by myelinated (probably Aδ-type) afferent fibers. Oxidative stress and TRPA1 channels may be potential targets to treat peripheral ischemia-associated dysesthesia.
authors.affiliation: Department of Applied Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan (A.Sas., S.M., M.S., A.Sak., T.A., Y.Ku.); Department I, Pharmacology Research Laboratories II, Research Division, Mitsubishi Tanabe Pharma Corporation, Toda, Japan (K.K., H.Tan., Y.Ki.); and Laboratory of Organic and Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University, Sendai, Japan (Y.S., H.Tak.).
authors.forename: Atsushi
authors.initials: A
authors.lastname: Sasaki
authors.affiliation: Department of Applied Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan (A.Sas., S.M., M.S., A.Sak., T.A., Y.Ku.); Department I, Pharmacology Research Laboratories II, Research Division, Mitsubishi Tanabe Pharma Corporation, Toda, Japan (K.K., H.Tan., Y.Ki.); and Laboratory of Organic and Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University, Sendai, Japan (Y.S., H.Tak.).
authors.forename: Shizuka
authors.initials: S
authors.lastname: Mizoguchi
authors.affiliation: Department of Applied Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan (A.Sas., S.M., M.S., A.Sak., T.A., Y.Ku.); Department I, Pharmacology Research Laboratories II, Research Division, Mitsubishi Tanabe Pharma Corporation, Toda, Japan (K.K., H.Tan., Y.Ki.); and Laboratory of Organic and Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University, Sendai, Japan (Y.S., H.Tak.).
authors.forename: Kenta
authors.initials: K
authors.lastname: Kagaya
authors.affiliation: Department of Applied Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan (A.Sas., S.M., M.S., A.Sak., T.A., Y.Ku.); Department I, Pharmacology Research Laboratories II, Research Division, Mitsubishi Tanabe Pharma Corporation, Toda, Japan (K.K., H.Tan., Y.Ki.); and Laboratory of Organic and Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University, Sendai, Japan (Y.S., H.Tak.).
authors.forename: Mai
authors.initials: M
authors.lastname: Shiro
authors.affiliation: Department of Applied Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan (A.Sas., S.M., M.S., A.Sak., T.A., Y.Ku.); Department I, Pharmacology Research Laboratories II, Research Division, Mitsubishi Tanabe Pharma Corporation, Toda, Japan (K.K., H.Tan., Y.Ki.); and Laboratory of Organic and Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University, Sendai, Japan (Y.S., H.Tak.).
authors.forename: Akiho
authors.initials: A
authors.lastname: Sakai
authors.affiliation: Department of Applied Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan (A.Sas., S.M., M.S., A.Sak., T.A., Y.Ku.); Department I, Pharmacology Research Laboratories II, Research Division, Mitsubishi Tanabe Pharma Corporation, Toda, Japan (K.K., H.Tan., Y.Ki.); and Laboratory of Organic and Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University, Sendai, Japan (Y.S., H.Tak.).
authors.forename: Tsugunobu
authors.initials: T
authors.lastname: Andoh
authors.affiliation: Department of Applied Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan (A.Sas., S.M., M.S., A.Sak., T.A., Y.Ku.); Department I, Pharmacology Research Laboratories II, Research Division, Mitsubishi Tanabe Pharma Corporation, Toda, Japan (K.K., H.Tan., Y.Ki.); and Laboratory of Organic and Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University, Sendai, Japan (Y.S., H.Tak.).
authors.forename: Yurika
authors.initials: Y
authors.lastname: Kino
authors.affiliation: Department of Applied Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan (A.Sas., S.M., M.S., A.Sak., T.A., Y.Ku.); Department I, Pharmacology Research Laboratories II, Research Division, Mitsubishi Tanabe Pharma Corporation, Toda, Japan (K.K., H.Tan., Y.Ki.); and Laboratory of Organic and Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University, Sendai, Japan (Y.S., H.Tak.).
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Taniguchi
authors.affiliation: Department of Applied Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan (A.Sas., S.M., M.S., A.Sak., T.A., Y.Ku.); Department I, Pharmacology Research Laboratories II, Research Division, Mitsubishi Tanabe Pharma Corporation, Toda, Japan (K.K., H.Tan., Y.Ki.); and Laboratory of Organic and Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University, Sendai, Japan (Y.S., H.Tak.).
authors.forename: Yukako
authors.initials: Y
authors.lastname: Saito
authors.affiliation: Department of Applied Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan (A.Sas., S.M., M.S., A.Sak., T.A., Y.Ku.); Department I, Pharmacology Research Laboratories II, Research Division, Mitsubishi Tanabe Pharma Corporation, Toda, Japan (K.K., H.Tan., Y.Ki.); and Laboratory of Organic and Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University, Sendai, Japan (Y.S., H.Tak.).
authors.forename: Hiroki
authors.initials: H
authors.lastname: Takahata
authors.affiliation: Department of Applied Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan (A.Sas., S.M., M.S., A.Sak., T.A., Y.Ku.); Department I, Pharmacology Research Laboratories II, Research Division, Mitsubishi Tanabe Pharma Corporation, Toda, Japan (K.K., H.Tan., Y.Ki.); and Laboratory of Organic and Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University, Sendai, Japan (Y.S., H.Tak.) kuraisiy@pha.u-toyama.ac.jp.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Kuraishi
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D006614:Hindlimb / Q000098:blood supply*; D007511:Ischemia / Q000150:complications; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress / Q000502:physiology*; D010292:Paresthesia / Q000209:etiology / Q000378:metabolism*; D015427:Reperfusion Injury / Q000150:complications / Q000378:metabolism*; D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels / Q000378:metabolism*
chemical_list: D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels; C475685:Trpa1 protein, mouse