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 pathophysiology.
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
Methods: Articles on the pathophysiology of MDD, as well as on the endogenous opioidergic system and mitochondrial
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 provides
a relevant target for novel treatment development, as well as providing a focus for the integration of wider