Antidepressants and the endogenous opioid system.

The endogenous opioid system consists of three different G protein-coupled receptors, named mu-, delta- and kappa-opioid receptors (MOR, DOR, and KOR, respectively). These receptors are activated by over 20 distinct peptides produced from proenkephalin, prodynorphin, and proopiomelanocortin. The endogenous opioid system contributes to many important functions including analgesia, reward, and regulation of mood. A growing body of evidence links the opioid system with major depressive disorder. One strong line of evidence is that two different widely used antidepressants, tianeptine and ketamine, both interact with MOR; tianeptine as a full agonist, and ketamine as a positive allosteric modulator. Both of these drugs produce clinical antidepressant effects within hours or days. Buprenorphine, a partial MOR agonist commonly used for treating opioid use disorder, also shows promise as a rapid-acting antidepressant. While the conventional view is that major depressive disorder is caused by an imbalance of biogenic amine neurotransmitters, drugs that affect these neurotransmitter systems typically require weeks of dosing before showing antidepressant effects. Chronic antidepressant treatment of mice causes changes in gene expression. Interestingly, proenkephalin is one of the most highly upregulated genes following long-term treatment of mice with fluoxetine, a selective serotonin reuptake inhibitor. Taken together, these findings suggest that the opioid system plays an important role in major depressive disorder. In this review, we discuss the strengths, problems, and limitations of the studies, as well as areas in need of further investigation.