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

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 [11C]carfentanil to test the hypothesis that MOR system activation in response to social rejection and acceptance is altered in medication-free patients diagnosed with current major depressive disorder (MDD, n = 17) compared to healthy controls (HCs, n = 18). During rejection, MDD patients showed reduced MOR activation (e.g., reduced endogenous opioid release) in brain regions regulating stress, mood, and motivation, and slower emotional recovery compared to HCs. During acceptance, only HCs showed increased social motivation, which was positively correlated with MOR activation in the nucleus accumbens, a reward structure. Abnormal MOR function 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.

Deletion of the mu opioid receptor gene in mice reshapes the reward–aversion connectome

“…The key implication of MOR activity in dampening physical, emotional, and social pain, evidenced in human PET imaging studies (see ref. 43 and references therein), and our own FC analysis of live Oprm1-deficient mice, together suggest that pain relief may be a primary MOR function. Importantly, our data unequivocally reveal pronounced causal effects of a single gene on whole-brain FC in live animals, with subtle modifications of the tractography-based structural connectome.…”

The dopaminergic response to acute stress in health and psychopathology: A systematic review

“…Finally, the endogenous opioid system is involved in both physical (Bencherif et al, 2002;Zubieta et al, 2001) and psychological stress (Hsu et al, 2015;Hsu et al, 2013) and administration of a μ-opioid receptor agonist affects both cortical and subcortical DAergic activity Hagelberg et al, 2002a). Thus, while the role of the DA system in stress processing may be relevant for stress-related disorders, the ultimate goal remains to investigate how these various neurotransmitter systems operate in synchrony to orchestrate the stress response.…”

Molecular Pharmacology ofδ-Opioid Receptors

“…Thus, in addition to the analgesic, anxiolytic, d-Opioid Receptor Pharmacology and antidepressant actions (Ribeiro et al, 2005;Hsu et al, 2015) that were mentioned in previous sections, opioids also promote cell survival (Hayashi et al, 2002;Ma et al, 2005), cardioprotection (Ikeda et al, 2006;Tsutsumi et al, 2010;Headrick et al, 2015), neuroprotection (He et al, 2013b;Liu et al, 2015), modulation of the immune/inflammatory response (Neptune and Bourne, 1997;Hedin et al, 1999;Sharp, 2006;Wang et al, 2014), and wound healing (Bigliardi-Qi et al, 2006;Iaizzo et al, 2012;Bigliardi et al, 2015). At the cellular level, a majority of these responses are mediated by an evolutionarily conserved set of kinase cascades whose activation has been traditionally associated with receptor tyrosine kinases (RTKs) (Takeda et al, 2011).…”