2019 Fiscal Year Final Research Report

Elucidation of the mechanism underlying diabetic neuropathic pain and development of its new therapy: Examination from the viewpoint of spinal angiotensin system

Research Project

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Project/Area Number	17K08313
Research Category	Grant-in-Aid for Scientific Research (C)
Allocation Type	Multi-year Fund
Section	一般
Research Field	Pharmacology in pharmacy
Research Institution	Tohoku Medical and Pharmaceutical University
Principal Investigator	Tan-No Koichi 東北医科薬科大学, 薬学部, 教授 (20207260)
Co-Investigator(Kenkyū-buntansha)	中川西修東北医科薬科大学, 薬学部, 准教授 (50296018) 根本亙東北医科薬科大学, 薬学部, 助教 (80635136)
Project Period (FY)	2017-04-01 – 2020-03-31
Keywords	糖尿病性神経障害性疼痛 / アンジオテンシン変換酵素2 / アンジオテンシン (1-7) / Mas受容体 / 脊髄 / p38 MAPK / ストレプトゾトシン / ob/obマウス
Outline of Final Research Achievements	The decrease of pain threshold was observed concurrently with an increase in blood glucose levels in both streptozotocin (STZ)-induced type 1 diabetic mice and leptin deficient ob/ob mice, a well-known model for type 2 diabetes. The expression of angiotensin (Ang) converting enzyme 2 (ACE2), which produces Ang (1-7) from Ang II, and Mas receptors, the receptors for Ang (1-7), in the plasma membrane fraction of the lumbar dorsal spinal cord were decreased in both STZ and ob/ob mice. The intrathecal administration of Ang (1-7) into STZ and ob/ob mice reduced the decrease of pain threshold, and the reduction was prevented by a Mas receptor antagonist. These results indicate that the downregulation of spinal ACE2 is involved in diabetic neuropathic pain, and suggest that the Mas receptor agonists may be the promising novel therapeutic agents for the relief of neuropathic pain in diabetic patients.
Free Research Field	神経薬理学
Academic Significance and Societal Importance of the Research Achievements	糖尿病性神経障害の機序は非常に複雑であるため治療に難渋し、臨床上大きな問題となっている。新たな治療薬や治療法の開発は社会的に急務であるが、これらの開発に向けては糖尿病性神経障害性疼痛の発症・維持に関わる新たな分子メカニズムを明らかにし、新規標的分子を同定する必要がある。本研究において脊髄後角のACE2の発現量低下が糖尿病性神経障害性疼痛に関与していることを明らかとした。また、Mas受容体刺激薬が糖尿病性神経障害性疼痛に対する新規治療薬になり得る可能性を示唆した。これらの知見は糖尿病性神経障害性疼痛の新規治療薬の開発を目指す上で貴重な情報提供になると考える。