Opioid receptors: distinct roles in mood disorders

Abstract

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.

Figure 1. Opioid receptor knockout (KO) mice phenotypes in models of addiction and mood disorders

Behavioral modifications are summarized for each receptor constitutive KO mouse line. Important conclusions from these data are the following: mu opioid receptors (MORs) are key mediators of both natural and artificial rewards [12, 13, 15], and may show pro-depressant activity [16, 17] although this is not supported by the pharmacology. Kappa opioid receptors (KORs) mediatedysphoria, particularly under stressful conditions where the dynorphin/KOR activity is higher [26-28]. Delta opioid receptors (DORs) decrease levels of anxiety and reduce depressive-like behaviors [16], however, its role in reward remains debated [18-23]. Exhaustive reviews are available on the role of MORs in reward processes [1], the emerging roles of DORs in brain disorders [18], the potential of MORs and DORs as targets to treat addiction [140], and the role of KORs in stress-induced and pro-addictive behaviors or more general psychiatric disorders [141]. Abbreviations: CPA conditioned place aversion; CPP, conditioned place preference; MDMA, 3,4-methylenedioxy-N-methylamphetamine; M6G, morphine-6-glucoronide, the active metabolite of morphine; SA, self-administration; THC, delta-9-tetrahydrocannabinol.

Figure 2. Anatomical distribution of opioid receptors throughout neural circuits of mood in the rodent brain

(A) Schematic representation of main monoaminergic nuclei and projections forming neural circuitry of reward processing and emotional responses, as discussed in the present review. Dysfunction in the mesolimbic DA circuit [60] is mostly associated with anhedonia and reduced motivation at the level of ventral tegmental area (VTA) and nucleus accumbens (NAc). 5-HT and NA neurons originating from the dorsal raphe nucleus (DRN) and the locus coeruleus (LC) respectively, project widely throughout the brain with a main implication of hippocampal (Hipp), prefrontal cortex (PFC), nucleus accumbens (NAc) and bed nucleus of the stria terminalis (BNST) projection areas involved in mood disorders, while the amygdala (Amy) is a main brain region involved in emotional dysfunction [58]. (B) Mu, delta and kappa opioid receptors (MORs, DORs and KORs, respectively) show overlapping but distinct anatomical distributions in neural circuits of mood. (C) Absolute protein expression levels of MORs, DORs and KORs across relevant brain structures are shown (from [1]). Of note is that anatomical studies in humans have mainly addressed cortical networks and comparing human with rodent data is currently difficult. For example, MORs in the anterior insular and dorsal anterior cingulate cortex has been implicated in social rejection in humans [111], yet their role in animal models of social separation or stress remains unexplored. Also, human imaging studies reveal a role for MORs in the thalamus (Th) in MDD [139], a receptor population ignored so far in animal models. Abbreviations: Hb, habenula; Hyp, hypothalamus; ICx, insular cortex; MHb, medial habenula; Th, thalamus

Figure 3. Functional interactions between opioid receptors and monoaminergic systems relevant to mood control

Monoaminergic neurons synthesizing dopamine (DA), serotonin (5-HT) and nordrenaline (NA) originate in the brainstem and send axonal projections throughout the whole brain. These neurons are regulated by opioid receptors at multiple sites. Represented here are main receptor pools, where functional effects have been documented or proposed in the context of mood-related behaviors (see text for details). Other receptor populations may also contribute. In summary, activation of mu opioid receptors (MORs) expressed in the dorsal raphe nucleus (DRN) and ventral tegmental area (VTA) by local GABAergic interneurons disinhibit 5-HT [67-70] and DA [1] neurons. On the contrary, noradrenergic neurons are directly inhibited by MORs [83]. Chronic morphine treatment targets MORs in all these regions. Acute withdrawal from chronic morphine produces conditioned place aversion (CPA), which relies on increased activity of noradrenergic neurons targeting the bed nucleus of stria terminalis (BNST) [83]. Prolonged withdrawal from chronic morphine, or abstinence, leads to 5-HT dysfunction and progressive depressive-like behaviours [75, 76]. Kappa opioid receptors (KORs) expressed presynaptically in the nucleus accumbens (NAc) by 5-HT neurons are sufficient for KOR-induced CPA [80]. In addition, stress potentiates the activity of the dynorphin/KOR system, which targets both (i) DA neurons (and possibly 5-HT neurons) in the NAc to produce depressive-like behaviours [27], and (ii) 5-HT neurons in the DRN to mediate acute social avoidance [81]. Finally, evidence suggests that additional receptor populations are likely to be implicated in mood regulation: all 3 opioid receptors modulate BDNF activity and neurogenesis in the hippocampus (Hipp) [88], and KORs selectively control DA neurons projecting to the prefrontal cortex (PFC) [27].