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 a μ-opioid receptor (MOR) radiotracer to measure changes in MOR availability in vivo with positron emission tomography (PET) 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 play 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.

Background During emerging adulthood, alcohol and substance use peak. Previous research has suggested that prefrontal and subcortical brain volumes may relate to risk for development of substance abuse. Epidemiological studies indicate that early initiation of alcohol or drug use significantly increases the likelihood of later substance use disorder diagnoses. We hypothesized that frontal regions would be smaller in young adults with early substance use and related problems (early-risk, ER), compared with a control group without early use/problems (C). We further hypothesized that these volumes would be associated with more externalizing behaviors, an additional robust predictor of substance abuse. Methods One hundred and six subjects, ages 18–23, underwent high-resolution anatomical magnetic resonance image scanning. Individuals were categorized as C (n = 64) or ER (n = 42) using a composite-score of early alcohol/drug use and problems based on prospectively collected assessments; externalizing behaviors were also previously assessed during adolescence. Neuroanatomical volumes were compared between groups and correlated with behavioral measures. Results ER subjects exhibited more externalizing behaviors than their control counterparts. Total left frontal cortex and left superior frontal cortex volumes were significantly smaller in the ER group, controlling for family history of alcoholism and current substance use. Total gray matter volumes were negatively associated with substance risk score. Further, externalizing behavior score was negatively correlated with both left superior cortical and left total cortical volumes. Conclusions These findings suggest that smaller frontal cortical volumes, specifically the left superior frontal cortex, represent an underlying risk factor for substance abuse in emerging adults.

Acceptance into groups and intimate relationships is necessary for survival and emotional well-being. Thus, even everyday occurrences of social rejection (when one is not wanted or liked) can cause sadness, anxiety and social withdrawal. Studies using functional magnetic resonance imaging show that responses to social rejection and physical pain share some common neuronal pathways, leading to a theory of 'social pain'. This theory hypothesizes that the 'pain' of social rejection can be dampened by the endogenous opioids, particularly through the μ-opioid receptor (MOR) which alleviates physical pain, but is also known to regulate responses to social distress in several nonhuman species. To test this hypothesis in humans, we used a MOR radiotracer to measure changes in MOR binding potential (that is, in vivo receptor availability) with positron emission tomography during social feedback. We found that social rejection as well as acceptance activated the MOR system above baseline in different brain regions, showing that the endogenous opioid system responds to social feedback in humans. (a) Social rejection shown here activated the MOR system in the left amygdala. (b) Activation levels extracted from the left amygdala were positively correlated with the personality trait resiliency, suggesting that during rejection high-resilient individuals are more capable of MOR activation, which may be protective or adaptive. For more information on this topic, please refer to the article by Hsu et al. on pages 1211-1217.