Immediate Communication

Molecular Psychiatry (2015) 20, 193–200; doi:10.1038/mp.2014.185; published online 20 January 2015

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

D T Hsu1,2, B J Sanford2, K K Meyers3, T M Love2, K E Hazlett4, S J Walker5, B J Mickey2, R A Koeppe6, S A Langenecker7 and J-K Zubieta2,6

  1. 1Department of Psychiatry, Stony Brook University, Stony Brook, NY, USA
  2. 2Department of Psychiatry, The Molecular & Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI, USA
  3. 3Department of Psychology, Wayne State University, Detroit, MI, USA
  4. 4Department of Psychology, Marquette University, Milwaukee, WI, USA
  5. 5Department of Psychiatry, Oregon Health & Science University, Portland, OR, USA
  6. 6Department of Radiology, University of Michigan, Ann Arbor, MI, USA
  7. 7Department of Psychiatry, University of Illinois at Chicago, Chicago, IL, USA

Correspondence: Dr DT Hsu, Department of Psychiatry, Health Sciences Center, T10-040C, Stony Brook University, Stony Brook, NY 11794-8101, USA. E-mail:

Received 15 September 2014; Revised 10 October 2014; Accepted 17 November 2014
Advance online publication 20 January 2015



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 [11C]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.