Opioid receptors: distinct roles in mood disorders

Opioid receptors: distinct roles in mood disorders – Trends Neurosci. 2014 Mar – free full-text PMC article

The roles of opioid receptors in pain and addiction have been extensively studied, but their function in mood disorders has received less attention.

Accumulating evidence from animal research reveal that mu, delta and kappa opioid receptors (MORs, DORs and KORs, respectively) exert highly distinct controls over mood-related processes.

DOR agonists and KOR antagonists have promising antidepressant potential, whereas the risk-benefit ratio of currently available MOR agonists as antidepressants remain difficult to evaluate, in addition to their inherent abuse liability.  

At present, both human and animal studies have mainly examined MORs in the etiology of depressive disorders, and future studies will address delta and kappa receptor function in established and emerging neurobiological aspects of depression, including neurogenesis, neurodevelopment, and social behaviors.


Endogenous opioids and their receptors were discovered from the early use of opium in both medicinal and recreational practices.

Opiate drugs hijack a complex neuromodulatory system composed of three receptors, mu, delta and kappa, which interact with a family of endogenous opioid peptides known as β-endorphin, enkephalins and dynorphins.

Opioid receptors form a subfamily of G-protein coupled receptors (GPCRs), which also includes the homologous but non-opioid nociceptin/orphanin FQ receptor.

Both receptors and peptides are expressed throughout peripheral and central nervous systems.

Opioids play a central role in pain processing and regulate many other aspects of physiology that include

  • stress responses,
  • respiration,
  • gastrointestinal transit, as well as
  • endocrine and immune functions

The mood-regulating properties of endogenous opioids represent another main aspect of opioid physiology.

The potent euphoric effects of known opiate drugs, and the high density of peptides and receptors in limbic brain areas, set the opioid system as a central player in both reward processing and mood control (see Glossary), and a feasible target to treat emotional dysfunction.

The natural course of a depressive episode is remission (50% at one year), even in the absence of medical intervention. Unfortunately, 80% patients experience relapse within 15 years.

Depression is a worldwide leading cause of disability, expected to even worsen in the next decades. 

Today, opioids are re-entering the therapeutic arsenal for MDD (Major Depressive Disorder) treatment. Agonists such as buprenorphine are used in the specific contexts of refractory depression and depression-addiction comorbidity, and may have broader indications

Recent clinical and animal research data further strengthen the notion that endogenous opioids contribute to the etiology of mood disorders.

Here we will review both genetic and pharmacological approaches that reveal mu, delta and kappa opioid receptors as highly distinct players in reward processes and emotional responses, and very different targets for clinical intervention in MDD

Opioid receptors and the neurobiology of depression

Many neurotransmitter systems and brain sites are involved in the pathogenesis of depression and opioid receptors regulate a number of these aspects (see Figure 2A and 2B).

Relevant to depression, opioid receptors also regulate activity of the hypothalamus-pituitary-adrenal gland (HPA) axis, a major endocrine stress system. This aspect of opioid receptor function and implications for mood has been reviewed elsewhere.

Opioid receptors and depression in humans

Addiction-depression comorbidity

Comorbidity is extremely frequent in psychiatry, and the association between depression and addiction is one of the most classical clusters.

According to the self-medication hypothesis, depressed patients may take advantage of acute euphoric properties of drugs of abuse to overcome their depressed mood, a transient relief that bears its own risk of entering into dependence.

Conversely, repeated exposure to drugs of abuse triggers neuroadaptations in brain structures that contribute to mood homeostasis (such as the mesolimbic DA pathway), potentially leading to depressive disorders (substance-induced depressive disorder).

Numerous data now convincingly document both hypotheses, and the relationship between addiction and depression is undoubtedly bidirectional.

While acute MOR activation has euphoric and antidepressant-like effects in rodents, chronic MOR signaling appears as a major risk factor for depression: these properties align well with the self-medication hypothesis and substance-induced depressive disorders, respectively

Insights into the human disorder

Post-mortem autoradiographic studies have examined MOR binding in suicide victims who were mainly diagnosed with depression. MOR expression was increased in frontal and temporal cortex, as well as in caudate nuclei (compared with controls who died of sudden death but with no history of psychiatric disorder), suggesting that depression and suicide associate with higher MOR density.

Concluding remarks

As behavioral models in rodents get more sophisticated, and neurobiological mechanisms of mood disorders better understood, MOR, DOR and KOR appear as important and highly distinct players in the regulation of emotional states

In brief, animal studies show that

  • DOR improves mood states acutely,
  • KOR decreases mood after stress, and
  • MOR exerts contrasting effects on mood.

The risk-benefit balance of currently available MOR as antidepressants remains otherwise difficult to evaluate, partly due to their inherent abuse liability.

Finally, research on causal factors underlying mood disorders has mainly implicated MOR receptors in the etiology of depressive states.

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