The Role of VTA Dopaminergic Neurons in Chronic Peripheral Neuropathic Pain- induced Depressive-like Behavior

Abstract

Abstract Affective disorders, such as depression, are commonly associated with the development of chronic pain, but the underlying mechanisms still remain unclear. The dopaminergic system, located in the midbrain, is considered one of the regions where both painful and emotional processing overlap. This suggests a structural basis hypothesis for the comorbidity of chronic pain and depression, highlighting the interplay between nociceptive and affective processing. In this study, we assessed depressive-like behaviors and performed artificial interference of VTA (ventral tegmental area) dopaminergic neurons in a mouse model of chronic peripheral neuropathic pain induced by the spared nerve injury (SNI) model. After a 4-week duration of hyperalgesia and allodynia resulting from SNI, social isolation and other depressive-like behaviors were observed in the SNI group. Furthermore, the SNI mice displayed an excitatory increase in dopaminergic cell activity. This electrophysiological alteration was found to play a key role in the development and modulation of the chronic peripheral neuropathic pain-induced depressive-like phenotype. Considering the established pain and affective circuits, the neuroplastic changes and functional role of VTA dopaminergic neurons within these circuits may serve as potential targets for understanding and therapeutically addressing the development of depressive-like symptoms accompanied by prolonged pain syndromes in humans.