Opioid receptors: distinct roles in mood disorders

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 reveals 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 remains difficult to evaluate, in addition to their inherent abuse liability. To date, both human and animal studies have mainly examined MORs in the etiology of depressive disorders, and future studies will address DOR and KOR function in established and emerging neurobiological aspects of depression, including neurogenesis, neurodevelopment, and social behaviors.

Introduction

Endogenous opioids and their receptors were discovered from the early use of opium in both medicinal and recreational practices. Morphine, the most active ingredient of opium, has highly potent pain-relieving properties and remains the most widely used painkiller in modern medicine, despite a plethora of undesirable effects. Among these, abuse liability remains a limitation when undertaking opioid-based pain therapies. Heroin, the diacetylated morphine derivative, has even stronger addictive properties and, as a major illicit drug of abuse, represents a public health problem worldwide.

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) that also includes the homologous but non-opioid nociceptin/orphanin FQ receptor. Both receptors and peptides are expressed throughout peripheral and central nervous systems [1] and have been the subject of intense investigations for several decades. Opioids play a central role in pain processing and regulate many other aspects of physiology that include stress responses, respiration, gastrointestinal transit, and endocrine and immune functions [2]. 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 for treatment of emotional dysfunction [3].

Mood disorders are defined as a group of diagnoses in which mood disturbance is the main underlying feature. Among these, major depressive disorder (MDD) is a chronic relapsing disorder characterized by the repetition of major depressive episodes (MDEs). The natural course of a depressive episode is remission (50% in 1 year), even in the absence of medical intervention. Unfortunately, 80% of patients experience relapse within 15 years [4]. Depression is a worldwide leading cause of disability, expected to even worsen in the next decades [5]. In the early 1900s, an opioid cure was proposed for the treatment of depressed patients through progressive exposure to low doses of an opiate mixture. Although seemingly effective [6], this approach was hampered by the inherent addictive properties of available opiates, as is the case for pain treatment. Since the advent of monoamine-targeting drugs in the 1950s, the antidepressant utility of opiates has been considered less, and first-line treatments in modern medicine currently rely on selective serotonin reuptake inhibitors (SSRIs). However, SSRIs are effective in only 40–50% patients [7] and identification of new targets for therapeutic intervention remains a major challenge.

Today, opiates are re-entering the therapeutic arsenal for MDD treatment. Drugs such as buprenorphine are used in the specific contexts of refractory depression [8] and depression–addiction comorbidity [9], 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 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. The role of endogenous opioids has been partly reviewed elsewhere [10] and is only briefly mentioned when appropriate.