There are well-known species differences in the distribution of opioid receptors in the brain. In general, there is relatively less δ-opioid receptor binding in the human brain compared to the rat brain, and relatively more κ-opioid receptor binding [72]. As such, it is prudent to be careful in extrapolating results from rodent data to humans, and human mechanistic studies are highly desirable.

A number of different approaches have been used to investigate the mechanisms underlying opioid receptors and function in humans. Among them, the use of selective radioligands and positron emission tomography (PET) (Fig. 2), as well as genetic and pharmacological approaches, have resulted in major contributions to the field, particularly as it relates to the processing of emotions and social cues. These measures show receptor availability under baseline conditions, which reflects their concentration, minus receptor occupancy by the endogenous ligand—which for endogenous opioid systems is thought to be very low. In addition, PET studies involving experimental challenges have allowed for the quantification of neurotransmitter release. Under these kinds of experimental conditions, reductions in in vivo receptor availability after an acute challenge are thought to reflect neurotransmitter release and competition between the radiotracer and the endogenous ligand for the receptor sites, providing an indirect measure of presynaptic function.

Fig. 2 Positron emission tomography (PET) baseline measures of opioid receptor binding in humans [images averaged across a group of subjects (n < 20 for all groups)]. Images are color-coded according to the scale shown so that highest concentrations of the radiotracer are represented by red and lowest concentrations by black/purple. Binding maps in the coronal (top) and axial (bottom) view show greatest binding in the striatum and insular cortex for all radiotracers, except for the δ-opioid receptor antagonist: N1′-([11 C]methyl) Naltrindol. Left: μ-opioid receptor agonist: [11C]; Carfentanil; δ-opioid receptor antagonist: N1′-([11C]methyl) Naltrindol; κ-opioid receptor antagonist: [11C] LY2795050; nociceptin receptor: [11C]NOP-1A. Reproduced with permission [137,138,139]. NOP receptor agonist: [11C]NOP-1A, images provided by Rajesh Narendran Full size image

µ-Opioid receptors are widely distributed in the brain, and their location ostensibly overlaps with regions implicated in emotion regulation [14]. The µ-opioid receptor-selective radiotracer [11C]carfentanil has been commonly used to investigate the link between opioid neurotransmission and emotion regulation. In initial studies, Zubieta et al. used in vivo measures of µ-opioid receptors during a sadness induction paradigm, a stimulus, which does not activate objective measurements of stress (i.e., cortisol or ACTH release) but induces a temporary low mood state. This emotional challenge was associated with reductions in endogenous opioid neurotransmission in a widespread network of regions implicated in emotion regulation [73], which were associated with increases and reductions in negative and positive affect, respectively.

Several studies have linked baseline measures of µ-opioid receptor availability to the prediction of antidepressant treatment response. For example, Zubieta and colleague [74] found that reductions in µ-opioid receptor availability were associated with poor treatment response to an SSRI, as well as higher plasma levels of stress hormones (cortisol and ACTH), while an exaggerated sadness-induced opioid release in the rostral anterior cingulate cortex (ACC)-predicted SSRI non-response. Similar sadness-induced exaggerated responses in the rostral ACC were also observed in patients with borderline personality disorder [75], a clinical diagnosis characterized by severely disrupted affective processing and typically poor response to existing antidepressant medications.

In a later study, the same group investigated the role of opioid neurotransmission in the formation of placebo responses in patients with MDD [76]. This investigation followed-up on growing evidence linking the opioid system to placebo analgesia [77,78,79,80]. This study involved two placebo lead-in phases followed by an open antidepressant administration. The two oral placebos were identical, but described as having either active or inactive fast-acting antidepressant-like effects. Patients were studied with PET and the μ-opioid receptor-selective radiotracer [11C]carfentanil after each 1-week inactive and active oral placebo treatment. In this sample, reduced baseline µ-opioid receptor availability in the nucleus accumbens predicted a lack of response to SSRI antidepressant medication [76]. Furthermore, the capacity to activate endogenous opioid neurotransmission in response to expectations of improvement elicited by the administration of the oral placebo, predicted the response to both oral placebo and antidepressant treatments, explaining up to 40% of the variance in treatment responses. This evidence suggests that µ-opioid receptors are not only involved in the neurobiology of normal and pathological emotional, hedonic, and stress processing, but also the response to both pharmacological and cognitive mechanisms of treatment response.

In addition, human neuroimaging studies have established a link between opioid neurotransmission and the processing of social cues. Initial evidence suggested that social rejection and physical pain shared similar neural pathways [81]. These studies supported the hypothesis that the µ-opioid receptor system could be involved in regulating other forms of non-painful stressor (i.e., social “pain”). This hypothesis was first tested in healthy volunteers using a social feedback task in response to social rejection and acceptance cues and the quantification of regional µ-opioid receptor availability. Greater opioid release in regions involved in emotion regulation during social rejection was significantly associated with higher scores in resiliency traits as well as reduced negative affect, consistent with an adaptive role of endogenous opioid neurotransmission on these processes [28, 82]. Not surprisingly, in a follow-up study, patients with depression, compared to controls, had reduced opioid release in similar regions [82]. This evidence suggests that the endogenous opioid system, in particular μ-opioid receptors, has a key role in the processing of social cues which seems to be particularly altered in patients with MDD (Fig. 3).

Fig. 3 Measure of changes in μ-opioid receptor availability in vivo with positron emission tomography (PET) during social rejection (not being liked by others) and acceptance (being liked by others). Compared to depressed patients, healthy controls showed greater rejection-induced opioid release in the nucleus accumbens, amygdala and midline thalamus. Reproduced with permission [82] Full size image

At the genetic level, several studies have investigated the relationship between variations within the human μ-opioid receptor gene (OPRM1) and depression-related traits and symptoms. The best studied genetic variant in the OPRM1 gene is a single-nucleotide polymorphism that changes the amino acid at position 40 in the N-terminal domain of the receptor from asparagine to aspartate [Asn40Asp, A118G, rs1799971 [83]]. Animal studies have suggested that the G118 allele is associated with loss of function of the receptor, lower surface receptor expression, decreased forskolin-induced cAMP activation, and lower agonist-induced MOPR activation [84, 85]. In a human PET study, 118G allele carriers (G-carriers), compared to A/A homozygotes, had an overall brain reduction of baseline μ-opioid receptor availability in regions implicated in pain and affective regulation. G-carriers also reported higher trait neuroticism and depression scores, which were inversely correlated with the in vivo brain measures of receptor concentrations [86]. G-carriers have also shown blunted cortisol responses to stressors, but greater cortisol responses to naloxone administration, suggesting differences in receptor affinity in G allele carriers [87]. Furthermore, G-carriers had greater reactivity to social rejection in the dorsal ACC and anterior insula, where the dorsal ACC activity in response to social rejection further mediated the relationship between the A118G polymorphism and dispositional sensitivity to rejection [88]. Therefore, G-carriers, possibly through a lower expression of µ-opioid receptors and a reduced capacity to release endogenous opioids, may have greater vulnerability for depressive-like symptoms and poorer treatment responses to SSRI treatment [74, 86].

Despite strong preclinical evidence, little is known about the role of δ-, κ-, and NOP receptors in the neurobiology and the mechanisms involved in the response to treatment in mood disorders. The localization of δ-opioid receptors in the amygdala is consistent with their modulation of fear and anxiety states [89], whereas localization in the cortex and hippocampus is consistent with their potential antidepressant effects [54]. On the other hand, and consistent with its role regulating reward, pain, and emotional processing, κ-opioid receptors are present in the deep layers of cortical regions and in the striatum, hippocampus, amygdala, and thalamus [90], where NOP receptors are also localized [66]. However, the lack of availability of specific δ-, κ- and NOP- agonists or antagonists for human administration, as well as the limited availability of selective radiotracers, has limited the understanding of these systems in clinical populations. A selective δ-opioid receptor antagonist [[11C]-methyl-naltrindole [91]] and several selective κ-opioid receptor radioligands (e.g., agonist ligands: [11C]-GR89696, [11C]-GR103545; antagonist ligands: [11C]-MeJDTic, [11C]-LY2795050 or [11C]-LY2459989) [92], are available for human use, but yet have not been applied to mood disorders. The failure of initial proof-of-concept clinical studies using δ-opioid receptor agonists [51], as well as a higher risk of producing convulsions [51], might have discouraged clinical mechanistic studies. Similarly, the use of the NOP receptor antagonist radiotracer [11C] (S)-3-(2′-fluoro-6′,7′-dihydrospiro[piperidine-4,4′- thieno[3,2-c]pyran]-1-yl)-2-(2-fluorobenzyl)-N-methylpropanamide (NOP-1A) has been successfully validated for use in human PET studies [93, 94], as well as clinical populations [95]. Still, the mechanisms through which NOP receptors modulate mood or anxiety disorders in humans, as suggested in clinical studies [71, 96] are currently unknown.