Neural circuitry remodeling in chronic pain and depression comorbidity: Toward an emotion-perception integration network model

Chronic pain (CP) and major depressive disorder (MDD) are highly disabling global diseases, and their high comorbidity creates a bidirectional vicious cycle, significantly exacerbating functional impairment and treatment resistance. Multidisciplinary evidence suggests that the comorbid nature arises from deep functional coupling and neural network remodeling between the sensory-pain and emotional systems, rather than merely a symptom overlap. Neuroimaging, animal models, and neuromodulation studies demonstrate that key brain regions, including the prefrontal cortex (PFC), anterior cingulate cortex (ACC), amygdala, hippocampus, insula, and reward system, show consistent abnormalities in the comorbid state, creating a cross-brain network that jointly regulates pain, emotion, and cognition. This paper systematically reviews the central structures, neural circuits, and neurotransmitter regulatory mechanisms of CP-MDD comorbidity and proposes an integrated emotion-perception coupling network model. We highlight the mechanisms and translational potential of multi-pathway intervention strategies, with a focus on neuromodulation techniques (rTMS, tDCS), combined with ketamine, BDNF modulators, and anti-inflammatory drugs. Additionally, it is emphasized that future research must integrate multimodal imaging, multi-omics data, and computational modeling to establish a mechanism-driven personalized stratification system. With the support of high spatiotemporal resolution brain connectomics technology, this will facilitate the transition from a 'symptom control' to a 'mechanism repair' paradigm in treating comorbidities. • Chronic pain and depression share overlapping neural circuitry dysfunction. • We propose an emotion–perception integration network model for comorbidity. • Circuit-level remodeling involves prefrontal–limbic–brainstem pathways. • Bidirectional modulation between pain and mood circuits sustains comorbidity. • Multimodal interventions target shared nodes and improve clinical outcomes.