Chronic neuropathic pain (NP) is a condition characterized by persistent nociceptive sensitization that often leads to long-lasting cognitive and emotional impairments, believed to stem from changes in brain circuits. In our previous work, we showed that neuronal density, assessed through NeuN immunofluorescence, was largely preserved in cortical and hippocampal regions, suggesting that overt cell loss is not a major driver of NP-associated cognitive/emotional symptoms. To investigate alternative potential neuropathological processes in NP, we analyzed the levels of TDP-43, a protein key for neuronal function that is implicated in neurodegenerative diseases. TDP-43 is a RNA-binding protein that regulates RNA metabolism at multiple levels. Our single-cell analysis of total and nuclear TDP-43 neuronal immunoreactivity revealed a significant increase within the somatosensory cortex (SSC) and hippocampal CA1 area. In contrast, neuronal TDP-43 immunostaining was reduced in the motor (MC), anterior insular (AIC), and prefrontal (PFC) cortices. Furthermore, the nuclear / cytoplasmic TDP-43 ratio was reduced not only in PFC but also in hippocampal CA1 and dentate gyrus (DG) areas, indicating pathological subcellular redistribution. These results uncover a novel region-specific dysregulation of TDP-43 in a chronic NP model, suggesting that cognitive/emotional behavioral alterations might be linked to impaired TDP-43 function due to changes in protein levels and mislocalization.