Up-regulation of acid-sensing ion channel 1a in the anterior cingulate cortex by TNF-α/NF-κB pathway contributes to diabetes-related pain

Effective treatment strategies for diabetes-related pain are limited due to its complex pathogenesis, particularly brain mechanisms underlying this disease. The acid-sensing ion channel 1a (ASIC1a) emerges as a key player in the development and treatment of various types of pain. Here, we investigated the role of ASIC1a in diabetes-related pain and its molecular mechanisms in the anterior cingulate cortex (ACC). Our findings demonstrate that the up-regulation of ASIC1a expression drives enhanced activity of excitatory glutamatergic neurons in the ACC (ACC^Glu), promoting the development of pain hypersensitivity in streptozotocin (STZ)-induced diabetic male mice. Pharmacological inhibition and genetic knockout of ASIC1a in ACC^Glu neurons significantly reduced neuronal activity and alleviated mechanical and thermal pain sensitizations in STZ-induced diabetes. Furthermore, increased levels of TNF-α in the ACC up-regulated ASIC1a through triggering NF-κB pathways, which led to the development of diabetes-related pain. Notably, the clinically used medication, infliximab, exhibited therapeutic effects on diabetes-related pain via its influencing on TNF-α/NF-κB/ASIC1a pathway in STZ mice. Collectively, this study identifies ASIC1a as a potential therapeutic target for diabetes-related pain, and the neutralization of TNF-α leads to pain relief through the TNF-α/NF-κB/ASIC1a pathway in the ACC. These findings hold promise for the development of the new clinical therapeutic strategies for diabetes-related pain.