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Title: Hypoxia-induced sensitisation of TRPA1 in painful dysesthesia evoked by transient hindlimb ischemia/reperfusion in mice
Authors: So, Kanako  kyouindb  KAKEN_id
Tei, Yuna
Zhao, Meng
Miyake, Takahito  kyouindb  KAKEN_id  orcid (unconfirmed)
Hiyama, Haruka
Shirakawa, Hisashi  kyouindb  KAKEN_id  orcid (unconfirmed)
Imai, Satoshi  kyouindb  KAKEN_id
Mori, Yasuo  kyouindb  KAKEN_id
Nakagawa, Takayuki  kyouindb  KAKEN_id  orcid (unconfirmed)
Matsubara, Kazuo  kyouindb  KAKEN_id
Kaneko, Shuji  kyouindb  KAKEN_id  orcid (unconfirmed)
Author's alias: 宗, 可奈子
中川, 貴之
金子, 周司
Issue Date: 17-Mar-2016
Publisher: Nature Publishing Group
Journal title: Scientific Reports
Volume: 6
Thesis number: 23261
Abstract: Dysesthesia is an unpleasant abnormal sensation, which is often accompanied by peripheral neuropathy or vascular impairment. Here, we examined the roles of transient receptor potential ankyrin 1 (TRPA1) in dysesthesia-like behaviours elicited by transient hindlimb ischemia (15–60 min) by tightly compressing the hindlimb, and reperfusion by releasing the ligature. The paw-withdrawal responses to tactile stimulation were reduced during ischemia and lasted for a while after reperfusion. Hindlimb ischemia/reperfusion elicited spontaneous licking of the ischemic hindpaw that peaked within 10 min. The licking was inhibited by reactive oxygen species (ROS) scavengers, a TRPA1 antagonist, or TRPA1 deficiency, but not by TRPV1 deficiency. In human TRPA1-expressing cells as well as cultured mouse dorsal root ganglion neurons, the H[2]O[2]-evoked TRPA1 response was significantly increased by pretreatment with hypoxia (80 mmHg) for 30 min. This hypoxia-induced TRPA1 sensitisation to H[2]O[2] was inhibited by overexpressing a catalytically-inactive mutant of prolyl hydroxylase (PHD) 2 or in a TRPA1 proline mutant resistant to PHDs. Consistent with these results, a PHD inhibitor increased H[2]O[2]-evoked nocifensive behaviours through TRPA1 activation. Our results suggest that transient hindlimb ischemia/reperfusion-evoked spontaneous licking, i.e. painful dysesthesia, is caused by ROS-evoked activation of TRPA1 sensitised by hypoxia through inhibiting PHD-mediated hydroxylation of a proline residue in TRPA1.
Description: 「しびれ」による痛みのメカニズムを解明 -糖尿病や血流障害によるしびれ治療薬の開発に期待-. 京都大学プレスリリース. 2016-03-18.
Rights: This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit
DOI(Published Version): 10.1038/srep23261
PubMed ID: 26983498
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