Upregulation 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 because of its complex pathogenesis, particularly brain mechanisms underlying this disease. The acid-sensing ion channel 1a (ASIC1a) has emerged as a key player in the development and treatment of various types of pain. 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 upregulation of ASIC1a expression drives enhanced activity of excitatory glutamatergic neurons in the ACC (ACCGlu), promoting the development of pain hypersensitivity in streptozotocin (STZ)-induced diabetic male mice. Pharmacologic inhibition and genetic knockout of ASIC1a in ACCGlu neurons significantly reduced neuronal activity and alleviated mechanical and thermal pain sensitizations in STZ-induced diabetes. Furthermore, increased levels of tumor necrosis factor-α (TNF-α) in the ACC upregulated ASIC1a by triggering nuclear factor-κB (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 influence on TNF-α/NF-κB/ASIC1a pathway in STZ-treated mice. Collectively, this study identifies ASIC1a as a potential therapeutic target for diabetes-related pain and shows 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 new clinical therapeutic strategies for diabetes-related pain. ARTICLE HIGHLIGHTS: Upregulation of acid-sensing ion channel 1a (ASIC1a) expression in anterior cingulate cortex (ACC) glutamatergic (ACCGlu) neurons drives diabetes-related pain hypersensitivity in mice, and pharmacologic inhibition and genetic knockout of ASIC1a in ACCGlu neurons significantly reduce neuronal hyperactivity and alleviate pain. Tumor necrosis factor-α/nuclear factor-κB signaling in the ACC elevates ASIC1a expression, mechanistically linking neuroinflammation to pain development in diabetic mice. ASIC1a is a potential therapeutic target for diabetes-related pain, offering a pathway-specific strategy for treatment development.