Desensitization of TRPA1 by dimethyl itaconate attenuates acute and chronic pain in mice

作者：Sen Xu, Jia-Yue Zhao, Junyi Ma, Xia-Lin Cui, Jiahui Lin, Shiyu Sun, Sijia Liu, Guokun Zhou, Jiangtao Zhang, Peipei Kang, Ying Liu · 发表于：Frontiers in Pharmacology · 年份：2025 · DOI：10.3389/fphar.2025.1671461 · 被引用次数：4 · 研究领域：Ion Channels and Receptors、Pain Mechanisms and Treatments、Ion channel regulation and function

Introduction: Chronic pain remains a significant clinical challenge due to the limited efficacy of current analgesics. Dimethyl itaconate (DMI), a cell-permeable derivative of itaconate with known anti-inflammatory and immunomodulatory properties, has recently shown promise in alleviating pain. However, the mechanisms by which DMI modulates acute and chronic pain remain unclear. Methods: Calcium imaging was employed to assess the activation and desensitization effects of DMI on TRPA1 in hTRPA1-HEK293T cells and DRG neurons. Molecular docking analysis was conducted to evaluate the potential covalent binding sites between DMI and TRPA1. Behavioral assays were used to establish acute and chronic pain models in mice and to examine the analgesic effects of DMI in these models. Results: In the present study, we found that DMI directly activates and desensitizes the transient receptor potential ankyrin 1 (TRPA1) channel, a critical calcium-permeable ion channel implicated in various pain states. Molecular docking analysis and functional assays using calcium imaging revealed possible covalent interactions between DMI and key TRPA1 residue (cysteine 621). To further explore the possible therapeutic effects of DMI for chronic pain, we investigated the possible analgesic effects of DMI in multiple chronic pain mouse models. Single intraplantar injection of DMI induced transient mechanical hypersensitivity in a dose-dependent manner, while repeated injection of DMI failed to induce pain ...