The Opioid System: The Foundation for Social Risk and Reward

mu opioid receptor
mu opioid receptor
The opioid system is responsible for social pain and reward in the brain; therefore, understanding its underpinnings may help clinicians manage patients with depression and suicidal ideation.

How susceptible is the human brain to social inclusion and isolation? The opioid system, largely influenced by pain and rewards, has a direct relationship with the psychopathology of depression and suicide.1 Emerging evidence shows that people whose brains have increased reactivity to social exclusion and decreased reactivity toward social reward are at higher risk for suicide.1

Opioids do more than alleviate physical pain; they can also manipulate mammalian behavior. Because the brain’s opioid system controls both the social pain and social inclusion domains, it is responsive to pharmacologic manipulation with opioids such as morphine.1 The mu-, delta-, and kappa-opioid receptors regulate mood, stress responses, and social reward.1

“Opioids are re-entering the therapeutic arsenal,” said Pierre-Eric Lutz, MD, PhD, from the French National Centre for Scientific Research in Strasbourg, France.

“In the early 1900s, an opioid cure was proposed for the treatment of depressed patients through progressive exposure to low doses of an opiate mixture. Although seemingly effective, this approach was hampered by the inherent addictive properties of available opiates.”

Early Social Experiences

Human bonding is rooted in 4 distinct bond groups: parent-infant, couples, friends, and conspecifics or human strangers.2 The early bonding that infants experience with their mothers largely shapes their future relationships, all underpinned by hormones that are activated with human interaction.2

“If these systems are not functioning optimally in the mother, they don’t develop properly in the child (oxytocin, the stress response, immune function, and the brain basis of attachment and social functions),” said Ruth Feldman, PhD, from the Gonda Brain Sciences Center at Bar-Ilan University, Ramat Gan, Israel, and the Child Study Center at Yale University in New Haven, Connecticut. “Such dysfunction in attachment-related neurobiologic systems and social behavior were also found in depressed patients, not only mothers.”

The Evolutionary Foundation of Suicide

Like physical pain, social pain has evolved to an evolutionary adaptation.3 People who experience isolation early in life may develop psychological distress, which if occurring frequently and intensively could lead to depression and suicide, the ultimate escape from social pain.3

“A behavior as universal as suicide cannot be explained without some consideration of our evolutionary past,” said John F. Gunn III, PhD candidate from the department of family science and human development at Montclair State University in New Jersey. “By accepting that suicide, like many behaviors, has an evolutionary origin, it is my hope that we — clinicians, researchers, and laypersons alike — can shed some of the baggage and judgement that is often attached to those experiencing what is, ultimately, a natural reaction to the experience of intense psychological pain.”

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Opioid Agonists Promote Social Interest

To test the hypothesis that the mu-opioid system is responsible for social reward and social distress, Chelnokova and colleagues administered a mu-opioid agonist (morphine), a nonselective opioid antagonist (naltrexone), and placebo in 3 separate sessions to 30 healthy men who were shown pictures of men and women with varying levels of attractiveness and eye gaze. With the aid of eye-tracking devices, researchers found that participants given morphine fixated more on the photographs’ eye region vs those given naltrexone (P<.001).4 The eye area is associated with rich social information, so participants who focused on the eyes were engaging in pro-social behavior.4

“What we have uncovered is that an imbalance of the brain’s own opioid system (blocking the signaling) can reduce attention to others’ eyes in a lab context,” explained Siri Leknes, DPhil, professor of psychology at the University of Oslo, Norway. “Unfortunately, giving opioid drugs to patients with social anxiety or depression might not be a good solution overall due to risk of addiction, even though we would predict that moderate doses of these drugs could increase social perception.”

Altering Reactions to Social Distress

In a series of murine studies, Browne and colleagues sought to determine how pharmacologic therapy could ameliorate chronic social defeat stress.5 The tested drugs included buprenorphine, ketamine, fluoxetine, and CERC-501, an investigational agent. The researchers found that mice given buprenorphine significantly were able to reverse chronic social distress after 7 days, but this was not seen in those given ketamine or CERC-501.5 Fluoxetine also enabled the mice to defeat stress, but the effects were not immediate. The theory is that buprenorphine’s modulation of mu-opioid receptors and blocking of kappa-opioid receptors help the brain adjust to social distress.5

“The ability of buprenorphine to normalize social interaction deficits was associated with restoring normal opioid receptor function in key brain areas,” said Irwin Lucki, PhD, professor and chair of pharmacology at the Uniformed Services University in Bethesda, Maryland. “Targeting opioid receptors to restore normal opioidergic tone can be beneficial in treating subjects with social anhedonia following trauma or exposure to high-stress situations.”

“The reason buprenorphine may be so effective is that unlike traditional antidepressants, its mechanism does not directly involve monoamine neurotransmitters,” said Caroline A. Browne, PhD, research assistant professor at the Uniformed Services University. “Rather, it causes equipotent blockade of kappa-opioid receptors and partial agonist effects at mu-opioid receptors, both of which appear critical for neural circuits to restore social interaction deficits and reverse maladaptive behaviors caused by severe stress. For patients with a history of opioid use disorder that have experienced trauma or depression, buprenorphine may be the most appropriate and effective treatment for their symptoms.” 


  1. Lutz PE, Courtet P, Calati R. The opioid system and the social brain: implications for depression and suicide [published online July 26, 2018]. J Neuro Res. doi: 10.1002/jnr.24269
  2. Feldman R. The neurobiology of human attachments. Trends Cogn Sci. 2017;21(2):80-99.
  3. Gunn JF III. The social pain model: understanding suicide through evolutionary psychology. Crisis. 2017;38(5):281-286.
  4. Chelnokova O, Laeng B, Løseth G, Eikemo M, Willoch F, Leknes S. The µ-opioid system promotes visual attention to faces and eyes. Soc Cogn Affect Neurosci. 2016;11(12):1902-1909.
  5. Browne CA, Falcon E, Robinson SA, Berton O, Lucki I. Reversal of stress-induced social interaction deficits by buprenorphine. Int J Neuropsychopharmacol. 2018;21(2):164-174.