Activated microglia secretome and proinflammatory cytokines increase neuronal mu-opioid receptor signalling and expression.

Due to its potential role in processes which rely on mu-opioid receptor function, investigating the relationship between Mu-Opioid receptors (MORs), neuroinflammation, and glial cells has gained momentum. Traditionally, MOR activation has been associated with immunosuppression, but recent findings suggest a more nuanced, bidirectional relationship with the immune system. To further investigate this relationship, herein, we investigated the role of the activated microglia secretome and proinflammatory cytokines in neuronal MOR expression and signalling. Our results show that both microglial secretome and specific cytokines increase neuronal MOR expression and enhance the [D-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO)-induced MOR activation. We also show that DAMGO-induced neuroinflammation increases neuronal MOR expression, activation, and regulation. Our findings suggest a feedback loop between microglial activation, cytokine release, and neuronal MOR dynamics. Future research should delve into the temporal dynamics and functional implications of this relationship, particularly concerning clinically relevant opioids like morphine and fentanyl and pain management.