Elucidation of neuropathic pain associated with type 2 diabetes mellitus: Involvement of spinal angiotensin system and development of the novel therapeutic agents

2023 Fiscal Year Final Research Report

• Project/Area Number: 20K07074
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47040:Pharmacology-related
• 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): 根本 亙 東北医科薬科大学, 薬学部, 講師 (80635136)
• Project Period (FY): 2020-04-01 – 2024-03-31
• 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) / p38 MAPK / 脊髄 / ob/obマウス

Outline of Final Research Achievements

In the present study, using the leptin deficient ob/ob mouse as a type 2 diabetic model, we examined whether the spinal angiotensin (Ang) system was involved in naturally occuring diabetic neuropathic pain. Following the hyperglycemia, persistent hyperalgesia was observed. At 12 weeks of age, the expression of Ang-converting enzyme (ACE) 2 in the dorsal spinal cord was decreased in ob/ob mice. Moreover, the intrathecal administration of Ang (1-7) attenuated hyperalgesia in ob/ob mice. The phosphorylation of spinal p38 MAPK was also attenuated by Ang (1-7) in ob/ob mice. In conclusion, we revealed that the neuropathic pain observed in ob/ob mice involved p38 MAPK phosphorylation accompanied by the downregulation of Ang (1-7)-generating system in the spinal cord.

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。こ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。