Abstract: Objective To explore the effect of sodium rutin (NaR) on comorbid depressive symptoms (CDS) in chronic pain induced by selected neurological injury (SNI).Methods A model of comorbid depressive symptoms in chronic pain was established using C57BL/6J mice by SNI. The modeled mice were divided into two groups: a SNI model group and a SNI+NaR group. Those undergoing sham operation were defined as control group. Then, their mechanical pain was assessed by Von Frey fibers. Depression-like behaviors were evaluated by the forced swimming test (FST) and the tail suspension test (TST). The number of microglia in the medial prefrontal cortex was detected by immunofluorescence.Results Compared with the Sham group, the SNI group showed significantly reduced threshold of foot contraction (P<0.001), remarkably extended immobility time of the FST and TST 28 days after surgery (P<0.001), with depression-like behaviors; and an increased number of IBA1+ microglia in mPFC of mice (P<0.05). Compared with the SNI group, the SNI+NaR group, which was given NaR immediately after surgery, showed significant increases of the 50% paw withdrawal threshold (PWT) (P<0.01) and increases in the immobility time of FST and TST when continuous treatment for 28 days (P<0.05). The mice, which shown depression-like behaviors, were administered NaR 28 days after surgery, while the immobility time of FST was significantly reduced after 1 week NaR administration (P<0.001), and TST immobility time was significantly reduced after 2 weeks of NaR administration (P<0.001). The number of microglia in the medial prefrontal cortex two weeks after treatment significantly decreased (P<0.05).Conclusions Under the condition of SNI model, NaR relieves the chronic pain and improves behaviors of depression. NaR reversed the increase of microglia number in the mPFC, which may be one of the mechanisms of its antidepressant effect.