Researchers have found that differences in one of the brain’s systems which regulates physical pain may explain why social rejection hurts so badly for people with depression. The study used positron emission tomography––“PET” scanning––to examine brain activity during a simulated online dating scenario.

The findings, published January 20th in Molecular Psychiatry, revealed that following social rejection, lower levels of natural pain-killing endogenous opioids were released in the brains of people with major depressive disorder (MDD), compared to people without depression. The depressed group also showed a different pattern of opioid activity in the brain’s reward centers during positive social interactions.

This builds on previous work by the research team, which includes several current and former NARSAD grant recipients. The study demonstrates that the experience of emotional hurt during rejection is mediated by the “mu-opioid receptor system,” the same system that works to ease physical pain and other stressors. This system helps dampen pain through the release of natural painkilling opioids into the space between brain cells.

“Altered opioid activity in depression may hinder emotional recovery from negative social interactions and decrease pleasure derived from positive interactions,” the research team reported. “Both effects may reinforce depression, trigger relapse, and contribute to poor treatment outcomes.”

The team was led by Jon-Kar Zubieta, M.D., Ph.D., of the University of Michigan Medical School. Dr. Zubieta is a Foundation Scientific Council member, 2002 and 2004 recipient of a NARSAD Independent Investigator Grant, and 2013 recipient of a NARSAD Distinguished Investigator Grant. The lead author on the study was David T. Hsu, Ph.D., of Stony Brook University, a 2010 NARSARD Young Investigator grantee. Scott A. Langenecker, Ph.D., of the University of Illinois at Chicago and a 2007 NARSARD Young Investigator grantee, also contributed.

The study was relatively small, but used sophisticated technologies to detect chemical changes in the brain. Seventeen medication-free patients with major depressive disorder and 18 non-depressed adults took part. Before being scanned, participants viewed photos and profiles of hundreds of adults and selected people  they would be most interested in dating romantically, similar to online dating. While in the PET scanner, participants were informed as to whether the individuals they were interested in rejected them or liked them.

While all the people who took part in the study reported feeling sad following rejection, the PET scans of depressed people showed reduced opioid activity in brain regions that regulate stress, mood, and motivation. In situations where they were liked back, only non-depressed people showed an increased desire for social interaction and opioid activity in the nucleus accumbens, a brain structure involved in reward and positive emotions. The depressed participants still reported feeling happy and accepted upon being liked, but this rush dissipated more quickly.

Those who took part in the study were told beforehand that the online dating scenario was not real. But the simulated task still produced a different emotional and chemical response across the two groups. These findings suggest a potential target for the development of new and innovative treatments for depression. “This may be a mechanism for slower or incomplete recovery from rejection and poorly sustained engagement in positive social interactions,” the research team reported. “The present study supports further investigation of the interaction between this system, social environment, and the pathophysiology and maintenance of major depression.”

Read the abstract.