The central amygdala as a pathological hub: A multi-level review of pain-emotion comorbidity

Chronic pain frequently coexists with emotional disorders such as anxiety and depression, thereby imposing a considerable global burden. This review aims to establish the central amygdala (CeA) as the primary neural hub regulating pain-related comorbidities. Existing evidence demonstrates that the CeA shapes both the sensory-discriminative and emotional-motivational dimensions of pain by integrating ascending pain inputs and descending regulatory outputs. At the cellular level, functionally antagonistic GABAergic neuronal populations within the central lateral capsular division (CeLC) exhibit abnormal plasticity during chronic pain, which disrupts emotional homeostasis. Key molecular mechanisms within the CeA include neuropeptide signaling, regulation of ionotropic and metabotropic glutamate receptors, and opioid receptor dynamics, all of which often display lateralization and state dependence. Moreover, neuroimmune dysregulation within the CeA and epigenetic modifications contribute substantially to the persistence of pain-emotion comorbidities. By integrating evidence across neural circuits, cells, molecules, immune responses, and epigenetics, this multi-level review positions the CeA as a critical convergence point and promising therapeutic target for alleviating the intertwined suffering of chronic pain and emotional disorders.