Establishment of animal models for elucidating the mechanism underlying dysesthesia

2014 Fiscal Year Final Research Report

• Project/Area Number: 25670285
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Pain science
• Research Institution: Kyoto University
• Principal Investigator: NAKAGAWA Takayuki 京都大学, 医学(系)研究科(研究院), 准教授 (30303845)
• Co-Investigator(Renkei-kenkyūsha): KANEKO Shuji 京都大学, 薬学研究科, 教授 (60177516) ; SHIRAKAWA Hisashi 京都大学, 薬学研究科, 准教授 (50402798) ; MORI Yasuo 京都大学, 工学研究科, 教授 (80212265)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Keywords: しびれ / 疼痛 / 動物モデル / 感覚神経 / TRPA1 / オキサリプラチン / 虚血再灌流 / 低酸素

Outline of Final Research Achievements

Oxaliplatin, a platinum-based chemotherapeutic agent, causes an unusual acute peripheral neuropathy triggered by cold in almost all patients within hours after its infusion. We found that oxaliplatin induced rapid-onset cold hypersensitivity in mice, which may represent painful dysesthesia considering the drug sensitivity to analgesics. Furthermore, we established another mouse dysesthesia model that transient hindlimb ischemia-reperfusion evoked spontaneous licking behavior, which was accompanied with hypoesthesia against tactile stimuli. TRPA1, a polymodal nociceptor expressed on primary sensory neurons, is involved in both painful dysesthesia models. Furthermore, we found that oxalate, a metabolite of oxaliplatin, or hypoxia induced TRPA1 sensitization to reactive oxygen species by inhibition of prolyl hydroxylase-mediated hydroxylation of a N-terminal proline residue 394 in TRPA1. In this study, we elucidated the molecular mechanism underlying an aspect of painful dysesthesia.

Free Research Field

薬理学、行動薬理学、神経薬理学、疼痛学