〔Abstract〕 Objective To explore whether the locus coeruleus(LC) mediates the pain in mice with depressive-like behaviors and underlying mechanisms.Methods Male C57BL/6J mice were randomly divided into two groups,including control and chronic restraint stress(CRS) group.Novelty-suppressed feeding test,tail suspension test and forced swimming test were used to assess the formation of depressive-like behaviors and the establishment of CRS model.The mechanical pain threshold of mice was detected by Von Frey brush test.LC neuronal activity was detected by c-Fos immunofluorescence staining.Neuronal excitability in LC was detected using electrophysiology of isolated brain slices.The influence on pain and depressive-like behaviors was identified by chemogenetics in LC.Results Compared with the Control group,CRS mice displayed significant depressive-like behavior after 3 weeks of CRS(CRS 3W),and the model was successful;CRS 3W mice showed a significant decrease in mechanical pain threshold and developed mechanical pain sensitivity.A lot of c-Fos+cells of LC was observed in CRS 3W mice,90% of them were noradrenergic neurons.Compared with the Control group,the neuronal excitability of noradrenergic neurons decreased in LC of CRS 3W mice.Compared with the Control group,chemogenetic activation of the LC noradrenergic neurons significantly reduced mechanical pain sensitization in CRS 3W mice.Conclusion The excitability of noradrenergic neurons in LC of CRS 3W mice decreases,and chemogenetic activation of noradrenergic neurons in LC can relieve pain sensitization in CRS 3W mice.