Response of the μ-opioid system to social rejection and acceptance
Authors: R A Koeppe
J-K Zubieta
B J Sanford
D T Hsu
H Wang
T M Love
J K Crocker
S T Korycinski
L Ni
B J Mickey
S A Langenecker
K E Hazlett
S J Walker
K K Meyers
Journal: Molecular Psychiatry (2013)
Discipline: NEUROSCIENCE & BEHAVIOR
Keywords: endogenous opioid system; social rejection; social acceptance; μ-opioid receptor; MOR activation
Affiliations: Department of Psychiatry, The Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI, USA.

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. 

Retracted: No

PubPeer comments:
 How were the VOIs derived? The spherical VOIs are centered on coordinates that are very close to the peak coordinates, and the sphere radii themselves are curious. Not all VOIs are spherical, either, there is an atlas VOI bounded within a border, for instance. How did the authors decide on these VOIs? Are the results still significant if the very small VOIs are enlarged at all (eg: 3mm to 4mm)? This paper stretches the number of  *a* *priori* VOIs that can be evaluated without needing to correct for multiple comparisons. Can an argument can be made for low power due to small sample? The DF values change throughout the manuscript, was there undocumented removal of data? , 
 Some of those t values couldn t be significant at p lt;.05 with FWE correction... Readers must dig to find out what PET outcome measure is being used.  MOR activation is misleading.  MOR activation was defined as the reduction in MOR BP from Baseline to Rejection (or Acceptance) block. makes it sound as though we re seeing displacement, but base scans were on a completely different day. , 
 3mm sphere means the roi was, what, 1.5 voxels in diameter? prob. centered the  roi around the peak activity to get sign... , 
 Dear authors, It would be appreciated if you would help us understand some of the analysis methods used in this paper. How many subjects were included in your analyses? The methods section reads  18 healthy volunteers and I see no mention of subjects excluded from analyses. This would yield 17 degrees of freedom for the t-tests reported in the results section, but the reported degrees of freedom are sometimes 16 and sometimes 15, but never 17. This is consequential to the reported significance of your results. For example, if only 17 participants were included in the analyses (thus giving 16 degrees of freedom for the t-tests), then a Pearson s r correlation of .48 would not be significant like reported. The figures do not help clarify this issue. For example, in Figure 3 b and c there are 18 data points, but in figure 3 e there are only 15 and in figure 3 d there appear to be only 17 (although it is unclear). I am further confused when evaluating the imaging results. How is the PAG significant with a t-value of 2.3, unless no familywise error corrections were made? Surely the authors corrected their statistics for the statistical tests run on 8 VOIs, further divided hemispherically (yielding 16 VOIs). Table 1 suggests that four different comparisons were made on these 16 individual VOIs, yielding 64 tests. The authors state  VOIs were applied to subtraction images in standardized space and alpha levels were family-wise error (FWE) corrected , which leaves me wondering how a t-value of 2.3 could ever have been significant. Can you please clarify this point? With gratitude, ,