<p>Chronic pain has emerged as the third leading health issue, following cardiovascular and cerebrovascular diseases and cancer. Clinically, patients with chronic pain often exhibit comorbid depression-like behaviors. However, the underlying mechanisms of chronic pain-related depression remain unclear. In this study, a chronic pain-related depression model was established in C57BL/6J, Vgat-Cre, and TH-Cre mice through sciatic nerve ligation (SNI) surgery. Viral-mediated DNA methyltransferase 1 (DNMT1) knockdown, optogenetic/chemogenetic modulation, electrophysiological recordings and molecular biology techniques were used to investigate the role of DNMT1 in regulating the projection from central amygdala GABAergic neurons (CeA^GABA) to locus coeruleus noradrenergic neurons (LC^NA) and its impact on chronic pain-related depression-like behaviors. Viral tracing identified LC as a major downstream target of the CeA. Immunohistochemical staining and electrophysiological recordings confirmed the functional synaptic connection between CeA-GABAergic neurons and LC-NAergic neurons. Behavioral assays showed the bidirectional modulation of pain-related depression phenotypes through LC-NAergic system: activation of LC-NAergic neurons induced depression-like behaviors, whereas their inhibition improved SNI-induced depression-like behaviors. Notably, CeA-GABAergic neurons were found to specifically innervate LC-NAergic neurons in mediating chronic pain-related depression-like behaviors. Furthermore, inhibition of the CeA^GABA → LC^NA circuit abolished the improvement of depressive behaviors in DNMT1 knockdown SNI mice, establishing DNMT1 as a key epigenetic regulator of this pathway. Taken together, our findings suggest that DNMT1 may suppress the GABAergic projections from the CeA to LC-NAergic neurons, thereby contributing to chronic pain-related depression-like behaviors. These findings provide novel insight into the circuit-related epigenetic basis of pain-depression comorbidity.</p>