Role of opioidergic system in regulating depression pathophysiology

Background: There is a clear clinical need for a better understanding of the biological underpinnings of major depressive disorder (MDD), allowing for the development of a treatment that is targeted to pathophysi-ology. Recent data indicate a role for the endogenous opioidergic system in MDD. This article reviews the roles and physiological interactions of the endogenous opioidergic system in the pathophysiology and heterogeneity of MDD. Methods: Articles on the pathophysiology of MDD, as well as on the endogenous opioidergic system and mito-chondrial function, form the basis of this review article. Results: The endogenous opioidergic system is intimately linked to wider MDD pathophysiology, including alterations in the gut microbiome, gut permeability, circadian rhythm, amygdala-prefrontal cortex interactions, and mitochondrial function. A decrease in the µ-/κ-opioid receptor ratio is an important mediator of the changes in mood in MDD, with effects not only on neurons, but also on glia and immune cells. Conclusion: The endogenous opioidergic system is intimately interwoven with MDD pathophysiology and pro-vides a relevant target for novel treatment development, as well as providing a focus for the integration of wider MDD pathophysiology.