• Wei Jiang, Peng Yu, Yu Yang, Meng-Tan Cai, Lin Gan, Kang Qu, Ying-Ying Cheng, and Ming Dong.
• Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Changchun, China.
• Pain. 2025 Feb 4.

AbstractNeuropathic pain (NP) is a chronic condition caused by nerve injuries, such as nerve compression. Understanding its underlying neurobiological mechanisms is critical for developing effective treatments. Previous studies have shown that Kinesin family member 1A (Kif1a) heterozygous deficient mice display sensory deficits in response to nociceptive stimuli. PI3K has been found to mitigate these sensory deficits by enhancing Kif1a transcription, highlighting KIF1A's key role in sensory pain. However, the exact mechanism through which PI3K regulates KIF1A expression in relation to pain remains unclear. In this study, we observed a significant increase in PI3K/AKT/CREB (cyclic AMP response element-binding protein) protein levels in the dorsal root ganglia and spinal cord after chronic constriction injury in both male and female C57BL/6 mice. Notably, elevated levels of TET1, as well as Kif1a mRNA and protein, were detected in both male and female mice. Activated (phosphorylated-CREB) p-CREB recruited the DNA demethylase TET1, which interacted with the Kif1a promoter, reducing methylation and increasing Kif1a mRNA and protein expression. PI3K inhibition using wortmannin reversed the demethylation of Kif1a and decreased its expression in male mice. Furthermore, TET1 knockdown or overexpression significantly affected pain-related behaviors, as well as Kif1a methylation and transcription. Female mice given intrathecal injections of PI3K inhibitors exhibited similar molecular and behavioral outcomes as male mice. These findings offer new insights into NP mechanisms, suggesting that targeting the PI3K/KIF1A axis could be a promising therapeutic approach for NP treatment.Copyright © 2025 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.

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