Objective To observe the effects of low-dose dexmedetomidine (DEX) on chronic pain-related depression-like behavior in rats and on the N-methyl-D-aspartate receptor 2B subunit (NR2B) in the prefontal cortex (PFC). Methods Twenty-two adult rats were randomly divided into Sham group (n=6), spared nerve injury (SNI) group (n=6), SNI+normal saline (NS) group (n=5) and SNI+DEX group (n=5). All rats of SNI+NS group and SNI+DEX group were intraperitoneally injected with an equal volume of NS or low-dose DEX (20 μg/kg) within 8-14 days after modeling. The von Frey test was used to evaluate the pain withdrawal threshold (PWT), and force swim test (FST) was used to evaluate rats' depression-like behavior. The expression of NR2B in PFC of rats was detected by Western blotting. Results Compared with the Sham group, the rats in SNI group had decreased PWT on day 1, 3, 7 and 14 after surgery, increased right leg immobility time and decreased NR2B protein expression in PFC on day 15 after surgery, and the differences were statistically significant (P<0.01, P<0.01, P<0.05). Compared with the SNI+NS group, the PWT of SNI+DEX group showed no significant changes (P>0.05) on day 1 to day 14 after surgery, the right leg immobility time in FST on day 15 after surgery was significantly decreased (P<0.01), and the expression of NR2B in PFC was significantly increased (P<0.05). Conclusion Intraperitoneal injection of a low-dose DEX may alleviate depression-like behavior associated with chronic neuropathic pain in rats, and the mechanism may be related to the increase of NR2B protein in PFC.