Sasaki Atsushi, Mizoguchi Shizuka, Kagaya Kenta, Shiro Mai, Sakai Akiho, Andoh Tsugunobu, Kino Yurika, Taniguchi Hiroyuki, Saito Yukako, Takahata Hiroki, Kuraishi Yasushi
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.).
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.)
J Pharmacol Exp Ther. 2014 Dec;351(3):568-75. doi: 10.1124/jpet.114.217570. Epub 2014 Sep 16.
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.
我们通过行为学方法检测了小鼠外周缺血后感觉异常，并着重从氧化应激方面研究了其潜在的分子机制。用橡皮筋紧紧捆绑踝关节诱导后肢缺血，通过切断橡胶止血带实现再灌注。我们发现，缺血后的再灌注显著引发了对再灌注后肢的舔舐行为，而全身给予抗氧化剂N-乙酰-L-半胱氨酸和瞬时受体电位（TRP）A1通道阻滞剂HC-030031 [2-(1,3-二甲基-2,6-二氧代-1,2,3,6-四氢-7H-嘌呤-7-基)-N-(4-异丙基苯基)乙酰胺]可显著抑制这种行为。足底注射另一种抗氧化剂苯基-N-叔丁基硝酮也可显著抑制缺血后舔舐行为。TRPV1通道阻滞剂BCTC [N-(4-叔丁基苯基)-4-(3-氯吡啶-2-基)四氢吡嗪-1(2H)-甲酰胺]并不抑制缺血后舔舐行为。足底注射过氧化氢可引发后肢舔舐行为，而N-乙酰-L-半胱氨酸、苯基-N-叔丁基硝酮和HC-030031可抑制该行为。缺血后舔舐行为不受感觉C纤维化学性耗竭的影响，但吗啡可抑制该行为，吗啡已被证明可抑制背角神经元的C纤维和Aδ纤维诱发反应。有趣的是，加巴喷丁和普瑞巴林并不抑制缺血后舔舐行为，它们已被证明可抑制C纤维诱发反应而非Aδ纤维诱发反应。目前的结果表明，缺血-再灌注诱导氧化应激，激活TRPA1通道，从而引发缺血后舔舐行为。有人认为这种行为是由有髓鞘（可能是Aδ型）传入纤维介导的。氧化应激和TRPA1通道可能是治疗外周缺血相关感觉异常的潜在靶点。
