The endogenous opioid system, which alleviates physical pain, is also known to regulate social distress and reward in animal models. To test this hypothesis in humans (n=18), we used an μ-opioid receptor (MOR) radiotracer to measure changes in MOR availability in vivo with positron emission tomography during social rejection (not being liked by others) and acceptance (being liked by others). Social rejection significantly activated the MOR system (i.e., reduced receptor availability relative to baseline) in the ventral striatum, amygdala, midline thalamus and periaqueductal gray (PAG). This pattern of activation is consistent with the hypothesis that the endogenous opioids have a role in reducing the experience of social pain. Greater trait resiliency was positively correlated with MOR activation during rejection in the amygdala, PAG and subgenual anterior cingulate cortex (sgACC), suggesting that MOR activation in these areas is protective or adaptive. In addition, MOR activation in the pregenual ACC was correlated with reduced negative affect during rejection. In contrast, social acceptance resulted in MOR activation in the amygdala and anterior insula, and MOR deactivation in the midline thalamus and sgACC. In the left ventral striatum, MOR activation during acceptance predicted a greater desire for social interaction, suggesting a role for the MOR system in social reward. The ventral striatum, amygdala, midline thalamus, PAG, anterior insula and ACC are rich in MORs and comprise a pathway by which social cues may influence mood and motivation. MOR regulation of this pathway may preserve and promote emotional well being in the social environment.
Humans rely on acceptance into groups and intimate relationships for survival and emotional well being. Threats to this need, such as social rejection (i.e., being excluded or not liked by others), can cause social withdrawal, impulsivity, substance abuse and symptoms of anxiety and depression.1, 2, 3, 4 Research over the past decade has shown that social rejection and physical pain share similar neuronal pathways, leading to the theory of ‘social pain’.5, 6, 7, 8, 9 This theory suggests that responses to social rejection are regulated by endogenous opioids and the μ-opioid receptor (MOR), which alleviates physical pain, and is also known to regulate social distress in several non-human species.10, 11, 12, 13, 14
A few studies suggest a role for the endogenous opioid system in ameliorating the effects of social rejection in humans. A central analgesic reduced brain functional magnetic resonance imaging (fMRI) blood-oxygenation-level-dependent (BOLD) responses to social rejection,15 and variations in the MOR gene were associated with BOLD sensitivity to social rejection.16 However, regional changes in the MOR system in humans that may serve to reduce the experience of social rejection are not known. The MOR system also has an important role in social reward in animal models;17, 18, 19, 20 however, it is not known if the MOR system has a similar role in humans. To examine regional changes in the MOR system during social rejection and acceptance, we measured changes in MOR availability in vivo using [11C]carfentanil, a ligand with high and selective affinity for MORs,21 with positron emission tomography (PET).
Materials and methods
Participants were 18 healthy volunteers aged 18–48 years (13 female, 5 males; mean age±s.d., 32±12 years) screened for active medical illness and psychiatric disorders using the SCID-IV (Structured Clinical Interview for DSM-IV Axis I Disorders) non-patient version. No subjects were taking psychotropic medications, hormones or hormonal contraception in the 3 months before study. Phase of menstrual cycle was not controlled for given that MOR binding potential (BP) in vivo is not influenced by phase in the menstrual cycle.22 Study protocols were approved by the Institutional Review Board of the University of Michigan Medical School, and written informed consent was obtained.
Social feedback task
Several days before scanning, subjects completed an online personal profile that included age, major/occupation, a list of their interests, a short paragraph of their positive qualities and a picture of themselves. Scores for the trait Ego Resiliency23 were also obtained at this time. Subjects selected at least 40 online profiles of preferred-sex individuals with whom they would be most interested in forming an intimate relationship, from a collection of 500 profiles of men and women. For each profile, subjects answered two questions (‘Would I like this person?’ and ‘Do I think this person would like me?’) on a seven-point Likert scale from ‘definitely no’ to ‘definitely yes’. To increase feedback saliency, only profiles with the highest ratings for both questions were used. These strategies were chosen based on an fMRI study24 and another showing that social feedback from highly-rated, opposite-sex individuals (compared with low-rated or same-sex individuals) resulted in the greatest changes in brain activation.25 Seventeen subjects identified themselves as heterosexual and rated only opposite sex profiles; one bisexual female chose to rate only female profiles. Nine subjects reported being single, two divorced, five in a relationship and two married.
During the PET scan, subjects were presented with their highest-rated profiles along with feedback that they were not liked (Rejection) or liked (Acceptance) (Figure 1a). Rejection and Acceptance blocks were 24 min each and contained 12 unique trials of equal length with varying levels of rejection/acceptance (seven trials ‘definitely no/yes’, four trials ‘very likely no/yes’ and one trial ‘likely no/yes’). Baseline scans were included to compare MOR BP during the same postinjection time frame (Figure 1b). Baseline trials contained a similar visual presentation, with gray-scale blocks in place of the pictures, and profile information and feedback presented as ‘N/A’. This task did not involve deception, but subjects were asked to imagine that the profiles and feedback were real (see Supplementary Methods). During each trial, subjects reported on a five-point Likert scale how much they felt sad, rejected, happy and accepted (order randomized in each trial). Following each block, subjects were given a four-item questionnaire measuring their current desire for social interaction (see Supplementary Methods). All behavioral responses were obtained using a five-button response box.
PET and magnetic resonance imaging
Protocols for the acquisition and reconstruction for PET, and coregistration with structural MRIs are described in the Supplementary Methods. In brief, each subject completed two PET scans for comparing Rejection and Acceptance with Baseline blocks acquired during the same postinjection time frame (starting at either 5 or 45 min; Figure 1b), as previously described for other paradigms.26, 27 [11C]carfentanil, a ligand with high and selective affinity for MORs,21 was synthesized at high specific activity (>3000 Ci/mmol) and administered intravenously at the beginning of each scan. High-resolution structural MRIs were coregistered with MOR binding maps and used for spatial normalization to standard space (Montreal Neurological Institute, Montreal, QC, Canada).
Within-subjects paired t-tests (two-tailed) were performed to compare mean subjective ratings between blocks. Affect ratings were categorized as ‘sad and rejected’ (mean of the items ‘sad’ and ‘rejected’) and ‘happy and accepted’ (mean of ‘happy’ and ‘accepted’).
MOR activation was defined as the reduction in MOR BP from Baseline to Rejection (or Acceptance) block. This difference represents processes such as competition between radiotracer and endogenous opioids, changes in the conformational state of the receptor after activation or receptor internalization and trafficking, which are all related to endogenous neurotransmission.27 The main contrasts of interest were modeled using Statistical Parametric Mapping v.8 (SPM8) (Wellcome Institute of Cognitive Neurology, London, UK). For each subtraction analysis, one- or two-sample t-values were calculated for each voxel using a pooled smoothed variance across pixels.28
A priori volumes of interest (VOIs) were created using MarsBaR region of interest toolbox (version 0.38) for SPM8 and included structures that are rich in MORs and respond to physical pain and/or social rejection.8, 15, 16, 26 These included the ventral striatum (6 mm radius sphere centered at ±12, 13, −9 mm), amygdala (8 mm sphere at ±20, −2, −21 mm), anterior insula (6 mm sphere at ±43, 7, −2), midline thalamus (4 mm sphere at 0, −15, 6), periaqueductal gray (3 mm sphere at 0, −33, −11) and subgenual cingulate cortex (sgACC) (6 mm sphere at 0, 14, −8 mm). The dorsal anterior cingulate cortex (dACC) was constructed from the automated anatomical atlas29 using PickAtlas,30 with a rostral–caudal boundary of y=36, 0.16 A VOI in the pregenual anterior cingulate cortex (pgACC) (5 mm sphere at −3, 32, 2) was chosen from a previous study that showed peak MOR deactivation at this location during self-induced sadness.27 VOIs were applied to subtraction images in standardized space and α-levels were family-wise error (FWE) corrected. VOI data were also extracted with MarsBaR and correlated with the trait Ego Resiliency and behavioral changes.
During Rejection compared with matched Baseline block, subjects reported feeling more ‘sad and rejected’ (t16=5.11, P<0.001) and less ‘happy and accepted’ (t16=6.03, P<0.001) (Figure 1c). Significant MOR activation was found in the left and right amygdala, right ventral striatum, midline thalamus and periaqueductal gray (PAG) (Figure 2a and Table 1). No significant MOR deactivations were found. The trait Ego Resiliency was positively correlated with MOR activation during Rejection in the amygdala (left, r=0.48, P=0.04; right, r=0.54, P=0.02), PAG (r=0.66, P=0.003) and sgACC (r=0.65, P=0.003) (Figures 3a–c). Increased ratings for ‘sad and rejected’ was negatively correlated with MOR activation in the pgACC (r=−0.73, P<0.001; Figure 3d). Subjects reported a decreased desire for social interaction following Rejection compared with Baseline (t16=2.14, P=0.048); however, this change was not significantly correlated with MOR activation in the VOIs. During Acceptance compared with matched Baseline block, subjects reported feeling more ‘happy and accepted’ (t16=3.71, P=0.002), with no change in ‘sad and rejected’ (t16=0.87, P=0.40) (Figure 1d). Significant MOR activation was found in the right anterior insula and left amygdala (Figure 2b and Table 1), whereas significant deactivation was found in the midline thalamus and sgACC (Figure 2b and Table 1). Neither Ego Resiliency nor scores for ‘happy and accepted’ were significantly correlated with MOR activation in the VOIs. Subjects reported an increased desire for social interaction following Acceptance compared with Baseline (t15=2.91, P=0.01), and this change was positively correlated with MOR activation in the left ventral striatum (r=0.60, P=0.01; Figure 3e).
Further analysis showed that Rejection induced significantly greater activation than Acceptance in the right ventral striatum, bilateral amygdala, midline thalamus and sgACC (Figure 2c and Table 2). MOR activation was not significantly greater during Acceptance compared with Rejection in any VOIs (Figure 2d). In several structures, MOR activation during Rejection was positively correlated with MOR activation during Acceptance. Such correlations were found in the ventral striatum (left, r=0.85, P<0.001; right, r=0.54, P=0.02), midline thalamus (r=0.77, P<0.001), anterior insula (left, r=0.79, P<0.001; right, r=0.62, P=0.006) and dACC (left, r=0.86, P<0.001; right, r=0.92, P<0.001), but not in the amygdala, PAG, pgACC or sgACC.
In a follow-up analysis, Ego Resiliency and behavioral measures during Rejection or Acceptance compared with Baseline blocks were not significantly different between subjects who reported being single/divorced (n=11) vs in a relationship/married (n=7) (two-sample t-tests, P>0.10). During Rejection, MOR activations (Table 1) were not significantly different between those who were single/divorced vs in a relationship/married (P’s>0.36). During Acceptance, only MOR activation (Table 1) in the right anterior insula was greater in subjects who reported to be in a relationship/married compared with those who were single/divorced (t16=2.15, P=0.05).
This is the first study to show regional changes in the human MOR system in response to social rejection and acceptance. Social rejection produced greater overall MOR activation compared with acceptance. Higher trait resiliency predicted a greater magnitude of activation in the amygdala, PAG and sgACC, suggesting that MOR activation during rejection in these areas is protective or adaptive. During acceptance, MOR activation in the left ventral striatum was positively correlated with an increased desire for social interaction. As established in animal models, all of these structures have high levels of MORs,31, 32, 33, 34, 35 and comprise a pathway by which social stimuli may influence mood and motivation.36, 37, 38, 39
In support of the view that MOR activation is protective or adaptive, a greater predisposition for resiliency predicted a greater magnitude of MOR activation during rejection in the amygdala, PAG and sgACC (Figures 3a–c). MOR activation in the amygdala is associated with analgesia40 and reducing norepinephrine release,41 potentially to regulate emotional responses to arousing stimuli.42 Similarly, the PAG is a pivotal site for coordinating visceral and behavioral responses to pain and other stressors,43 and MOR-mediated signaling in the PAG attenuates pain and distress behaviors.44, 45, 46 Consistent with these roles for the amygdala and PAG, one study showed that scores from daily feelings of social rejection correlated with fMRI BOLD signal in these structures during a social exclusion task.47 BOLD signal in sgACC, an area strongly linked to sadness and major depressive disorder,48, 49 has also been shown to increase during social exclusion,50, 51 and predicts increases in depressive symptoms.52 Consistent with these data, this study found that during rejection, high-resilient individuals are more capable of MOR activation in the amygdala, PAG and sgACC, potentially serving a protective function by reducing rejection-induced neuronal activity in these regions.
During rejection, MOR activation was significantly increased in the right ventral striatum in the area of the nucleus accumbens (Figure 2a and Table 1). Although opioid activity in the nucleus accumbens is well known for its role in reward,53, 54 it also has a role in reducing physical pain,26, 55, 56 and may therefore have a similar role during social rejection. MOR activation during rejection was also significantly increased in the midline thalamus, which has among the highest levels of MOR BP in humans57 and displays the greatest MOR activation following different types of acute pain.26, 58 Animal studies show that the highest thalamic density of MORs is found in the paraventricular nucleus,35 a midline thalamic nucleus consistently and strongly activated following a wide variety of stressors, and involved in regulating the effects of repeated stress.59, 60 MOR-mediated signaling inhibits thalamic neurons61 and the paraventricular nucleus is specifically connected to structures involved in regulating stress responses, mood and motivation, including the nucleus accumbens, amygdala, PAG, anterior insula and sgACC.37, 38, 39 Thus, MOR activation in the midline thalamus may serve to coordinate the responses of multiple structures during social rejection.
The pattern of MOR activation in the amygdala, thalamus and ventral striatum during social rejection was similar to that during physical pain,26, 62 supporting the hypothesis that responses to social rejection and physical pain are regulated by overlapping neuronal pathways.5, 6, 7, 8, 9 In contrast, a previous study showed overall MOR deactivation when healthy adults made themselves feel sad by focusing on a sad autobiographical event, selected and rehearsed before scanning.27 In this study, 10 of the 14 subjects recalled the death of a loved one, three recalled romantic breakups and one a recent argument with a friend. Thus, differences in MOR activation between this study and the induced sadness study might be explained by different mechanisms associated with unrehearsed emotional responses during social feedback vs rehearsed bereavement. As the pattern of MOR activation during social rejection is similar to that of physical pain,26, 62 it is possible that naturalistic coping with an external stressor results in overall MOR activation compared with permissive, internally generated sadness, which results in MOR deactivation.27 Despite these differences, MOR activation in the pgACC was negatively correlated with increased ratings of negative affect during both social rejection (Figure 3d) and induced sadness,27 suggesting a common role for MOR activation in the pgACC in dampening the negative effect, regardless of how the emotion was elicited.
A few fMRI studies also suggest that external cues vs internally generated cues may account for some of the differences observed in MOR activation during social feedback vs induced sadness.27 In two fMRI studies where subjects were asked to view a photo of a romantic ex-partner and relive the rejection experience (i.e., a combination of external and internal cues), increased BOLD activation was found in the anterior insula and ACC,8, 63 whereas recalling sad thoughts about a recent romantic breakup (i.e., internal cues only) resulted in deactivation in areas including the insula and ACC.64 Thus, the pattern of activation found in the former fMRI studies8, 63 is more consistent to this study (all using external or a combination of external/internal cues), whereas the latter fMRI study is consistent to the MOR study using induced sadness27 (all using internal cues). However, combining the interpretation of results from MOR PET studies with fMRI studies is tentative, as the relationship between MOR activation and BOLD signal is not known.
The MOR system also has a role in mediating social reward. In humans, variations in the MOR gene were shown to be associated with social hedonic capacity,65 and a large body of animal work shows that MOR-mediated signaling has an important role in social reward.17, 18, 19, 20 This study showed increased MOR activation in the amygdala and anterior insula during acceptance (Figure 2b and Table 1), consistent with increased opioid activation observed in the amygdala during an amusing video clip,66 and in the anterior insula following amphetamine administration.67 Interestingly, MOR activation in the right insula was also greater in those who were in a relationship or married compared with those who were single or divorced. It is intriguing that those in relationships have greater MOR activation during social acceptance, suggesting that being in a social pair bond may promote a more responsive MOR system. However, given the limited number of subjects per group (n=7 and 11), this hypothesis needs to be confirmed in a larger sample size.
MOR activation in the left ventral striatum in the region of the nucleus accumbens was positively correlated with an increased desire for social interaction. This finding is consistent with a recent report showing that in adolescent rats, MORs but not δ- or κ-opioid receptors in the nucleus accumbens mediate social play behavior.20 This study also found significant MOR deactivation during acceptance in the midline thalamus and sgACC (Figure 2b and Table 1). In the thalamus, MOR deactivation during acceptance may serve to ‘permit’ the positive effects of acceptance. Consistent with this hypothesis, a previous study in rats showed that an MOR agonist injected into the medial thalamus raised the threshold for both pain and positive reinforcement.68 This hypothesis may also be particularly important for the sgACC, which is associated with anhedonia in major depressive disorder.49, 69
MOR activation during rejection showed positive correlations with MOR activation during acceptance in several areas, suggesting that the MOR system responds to both types of stimuli. This is consistent with animal studies showing that endogenous opioid release reduces distress during social separation, and facilitates positive emotions during play.10, 11, 12, 13, 14, 17, 18, 19, 20 This study further adds to this model by showing regional specificity in MOR activation during rejection and acceptance. Differences in the magnitude of MOR activation were found in specific areas during rejection compared with acceptance (Figure 2 and Tables 1 and 2). Furthermore, the areas where MOR activation correlations were not found (i.e., amygdala, PAG, pgACC, sgACC) were also the only areas that correlated with resiliency and negative affect during rejection (Figures 3a–d), suggesting that MOR activation in these structures were specific to rejection. Although it is also possible that the overall greater MOR activation during rejection was due to greater saliency of rejection compared with acceptance, the magnitude of affective change between the two conditions were not different (Figures 1c and d), and subjects reported that both conditions felt equally similar to real-life experiences (see Supplementary Methods). Future studies will need to establish a causal relationship between MOR activity and subjective feelings by pharmacologically manipulating the MOR system and measuring changes in regional MOR BP and affect.70, 71
This study found that MOR activation in the dACC was greater during rejection than during acceptance (Figure 2c). Although this activation did not reach statistical significance within the large dACC VOI, the location of the peak was similar to that in fMRI studies of social rejection,5, 8 suggesting that MOR activation has a role in regulating dACC activity during rejection. Surprisingly, MOR activation in anterior insula, which is activated in fMRI studies of rejection,9 was significant during acceptance but not rejection. This may suggest that MOR activation in the anterior insula, which may be involved in both negative and positive emotions,72 is more sensitive to social acceptance than rejection. This is consistent with one fMRI study showing that the anterior insula is activated while being liked by others.25 Future studies will need to investigate the relationship between BOLD and MOR activity in response to social rejection and acceptance.
This study demonstrates that social rejection and acceptance activate the MOR system in neuronal pathways regulating mood and motivation. The pattern of MOR activation during social rejection was similar to that previously found during sustained physical pain, suggesting an overlapping role for the MOR system in regulating both social rejection and physical pain. In addition, resiliency traits and subjective experiences were associated with MOR responses to rejection. On the other hand, social acceptance resulted in weaker MOR activation, and activation in the nucleus accumbens was significantly correlated with an increased desire for social interaction. Thus, the MOR system may have a dual role in reducing social distress and mediating social reward, as have been shown in animal studies. This study provides a first step towards understanding the neurochemical regulation of positive and negative social cues in humans, suggesting a potential mechanism for rejection sensitivity and social anhedonia in major depressive, social anxiety, substance use, eating, body dysmorphic and borderline personality disorders.73, 74, 75, 76
This research was supported by National Institute of Health Grants K01 MH085035 (DTH), K23 MH074459 (SAL), R01 DA022520 and R01 DA027494 (JKZ), a National Alliance for Research on Schizophrenia and Depression Young Investigator Award (DTH), pilot grants from the Michigan Institute for Clinical and Health Research (DTH), a Rachel Upjohn Clinical Scholars Award (DTH) and the Phil F Jenkins Foundation (JKZ).
Supplementary Information accompanies the paper on the Molecular Psychiatry website (http://www.nature.com/mp)