Chronic Pain and Comorbid Emotional Disorders: Neural Circuitry and Neuroimmunity Pathways

Chronic pain is a multidimensional experience that not only involves persistent nociception but is also frequently accompanied by significant emotional disorders, such as anxiety and depression, which complicate its management and amplify its impact. This review provides an in-depth exploration of the neurobiological mechanisms underlying the comorbidity of chronic pain and emotional disturbances. Key areas of focus include the dysregulation of major neurotransmitter systems (serotonin, gamma-aminobutyric acid, and glutamate) and the resulting functional remodeling of critical neural circuits implicated in pain processing, emotional regulation, and reward. Given the contribution of neuroimmune mechanisms to pain chronicity and mood disorders, we further conducted an in-depth investigation into the role of neuroimmune factors, including resident immune cells, infiltrating immune cells, and the release of inflammatory mediators. This review further discusses current therapeutic strategies, encompassing pharmacological interventions, neuromodulation, and integrative approaches, and emphasizes the necessity of targeted treatments that address both pain and emotional components. Finally, it identifies gaps in the current understanding and outlines future research directions aimed at elucidating the complex interplay between chronic pain and emotional disorders, thereby laying the foundation for more effective and holistic treatment paradigms.