In this study, we did not detect any significant changes among groups in the total ERK1/2 levels, but the levels of ERK1/2 phosphorylation in the DRGs, spinal cord, and hippocampus were significantly higher in the model than in the control group, indicating that the activation of this pathway might mediate pain and depression signal transduction in the case of DNP and MDD comorbidity. Here, MAPK3 is linked to depressive disorder.