Response of the μ-opioid system to social rejection and acceptance

Abstract

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.

Figure 1

Study design and behavioral results. (a) During the scan, the subject is presented with self-selected profiles (left) along with her own profile (right), viewed on a personal computer. The following information is presented in succession: the first line reminds the subject how much she liked this person, the second line reminds the subject that she believed this person would like her, the last line provides feedback that this person did not like her (Rejection shown here) or did like her (Acceptance). After each trial, subjects rate how they feel. (b) Each subject received an intravenous injection of [¹¹C]-labeled carfentanil and completed two scans for examining Rejection and Acceptance blocks, compared with Baseline blocks from the same post-injection time frame. The order of scans 1 and 2, and Rejection and Acceptance, were counterbalanced between subjects using the Latin Squares design to control for potential order effects. (c) Subjects reported feeling more “sad and rejected” during the Rejection block, and (d) more “happy and accepted” during the Acceptance block, compared to matched Baseline blocks (mean ± s.e.m). Consent was obtained by DT Hsu to publish the likenesses in this image.

Figure 2

Changes in MOR BP. (a) MOR activation during Rejection is shown in red-yellow, MOR deactivation in shades of blue. Greater activation was found in the right ventral striatum, bilateral amygdala, and midline thalamus. (b) Greater activation during Acceptance was found in the anterior insula and left amygdala, whereas greater deactivation was found in the midline thalamus and sgACC. (c) Greater activation during Rejection compared to Acceptance blocks was found in the right ventral striatum, bilateral amygdala, midline thalamus, sgACC and dACC. (d) Relatively little activation was found for the opposite contrast. For all images, contrast t maps are rendered onto a template brain in MNI space. Display threshold: p < 0.01, whole-brain uncorrected.

Figure 3

Extracted data from VOIs (red outlines) correlated with trait resiliency and state changes. MOR activation during Rejection correlated with Ego Resiliency in the (a) amygdala (b) PAG, and (c) sgACC, suggesting that high-resilient individuals are more capable of MOR activation in these regions during rejection. (d) Increased ratings for “sad and rejected” were negatively correlated with MOR activation in the pgACC (i.e., subjects who felt less “sad and rejected” had greater MOR activation during Rejection). (e) During Acceptance, increased ratings in the desire for social interaction were positively correlated with MOR activation in the left ventral striatum.