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      It still hurts: altered endogenous opioid activity in the brain during social rejection and acceptance in major depressive disorder

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          Abstract

          The μ-opioid receptor (MOR) system, well known for dampening physical pain, is also hypothesized to dampen 'social pain.' We used positron emission tomography scanning with the selective MOR radioligand [(11)C]carfentanil to test the hypothesis that MOR system activation (reflecting endogenous opioid release) in response to social rejection and acceptance is altered in medication-free patients diagnosed with current major depressive disorder (MDD, n=17) compared with healthy controls (HCs, n=18). During rejection, MDD patients showed reduced endogenous opioid release in brain regions regulating stress, mood and motivation, and slower emotional recovery compared with HCs. During acceptance, only HCs showed increased social motivation, which was positively correlated with endogenous opioid release in the nucleus accumbens, a reward structure. Altered endogenous opioid activity in MDD may hinder emotional recovery from negative social interactions and decrease pleasure derived from positive interactions. Both effects may reinforce depression, trigger relapse and contribute to poor treatment outcomes.

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          Does rejection hurt? An FMRI study of social exclusion.

          Naomi Eisenberger, Matthew Lieberman, Kipling D Williams (2003)
          A neuroimaging study examined the neural correlates of social exclusion and tested the hypothesis that the brain bases of social pain are similar to those of physical pain. Participants were scanned while playing a virtual ball-tossing game in which they were ultimately excluded. Paralleling results from physical pain studies, the anterior cingulate cortex (ACC) was more active during exclusion than during inclusion and correlated positively with self-reported distress. Right ventral prefrontal cortex (RVPFC) was active during exclusion and correlated negatively with self-reported distress. ACC changes mediated the RVPFC-distress correlation, suggesting that RVPFC regulates the distress of social exclusion by disrupting ACC activity.
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            Regional mu opioid receptor regulation of sensory and affective dimensions of pain.

            J Zubieta, Y Smith, J Bueller … (2001)
            The endogenous opioid system is involved in stress responses, in the regulation of the experience of pain, and in the action of analgesic opiate drugs. We examined the function of the opioid system and mu-opioid receptors in the brains of healthy human subjects undergoing sustained pain. Sustained pain induced the regional release of endogenous opioids interacting with mu-opioid receptors in a number of cortical and subcortical brain regions. The activation of the mu-opioid receptor system was associated with reductions in the sensory and affective ratings of the pain experience, with distinct neuroanatomical involvements. These data demonstrate the central role of the mu-opioid receptors and their endogenous ligands in the regulation of sensory and affective components of the pain experience.
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              Life event dimensions of loss, humiliation, entrapment, and danger in the prediction of onsets of major depression and generalized anxiety.

              F Butera, Jessica C. Gardner, John Hettema … (2003)
              Although substantial evidence suggests that stressful life events predispose to the onset of episodes of depression and anxiety, the essential features of these events that are depressogenic and anxiogenic remain uncertain. High contextual threat stressful life events, assessed in 98 592 person-months from 7322 male and female adult twins ascertained from a population-based registry, were blindly rated on the dimensions of humiliation, entrapment, loss, and danger and their categories. Onsets of pure major depression (MD), pure generalized anxiety syndrome (GAS) (defined as generalized anxiety disorder with a 2-week minimum duration), and mixed MD-GAS episodes were examined using logistic regression. Onsets of pure MD and mixed MD-GAS were predicted by higher ratings of loss and humiliation. Onsets of pure GAS were predicted by higher ratings of loss and danger. High ratings of entrapment predicted only onsets of mixed episodes. The loss categories of death and respondent-initiated separation predicted pure MD but not pure GAS episodes. Events with a combination of humiliation (especially other-initiated separation) and loss were more depressogenic than pure loss events, including death. No sex differences were seen in the prediction of episodes of illness by event categories. In addition to loss, humiliating events that directly devalue an individual in a core role were strongly linked to risk for depressive episodes. Event dimensions and categories that predispose to pure MD vs pure GAS episodes can be distinguished with moderate specificity. The event dimensions that preceded mixed MD-GAS episodes were largely the sum of those that preceded pure MD and pure GAS episodes.
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                Author and article information

                Journal
                Title: Molecular Psychiatry
                Abbreviated Title: Mol Psychiatry
                Publisher: Springer Science and Business Media LLC
                ISSN (Print): 1359-4184
                ISSN (Electronic): 1476-5578
                Publication date Created: February 2015
                Publication date (Electronic): January 20 2015
                Publication date (Print): February 2015
                Volume: 20
                Issue: 2
                Pages: 193-200
                Article
                DOI: 10.1038/mp.2014.185
                PMC ID: 4469367
                PubMed ID: 25600108
                SO-VID: b7f2414f-0293-411a-9d38-d55b9a3a2903
                Copyright © © 2015
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                http://www.springer.com/tdm

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