Inhibition of granulocyte ROS production by opioids prevents regeneration

Inhibition of regeneration and induction of healing are classic outcomes of tissue repair in adult mammals. Here, by using gain and loss of function experiments, we demonstrate that both endogenous and exogenous opioids prevent tissue regeneration in adults, by inhibiting the early reactive oxygen species (ROS) production occurring after lesion and required for regeneration. These effects can be overcome and regeneration induced by the use of an opioid antagonist. These results, obtained in both gold-standard adult zebrafish and a newly-developed model of regeneration in adult mammals, demonstrate that this mechanism can be considered as a general paradigm in vertebrates. In addition, we show that opioids act via signaling through peripheral mu-receptors expressed on granulocytes. This work clearly demonstrates the deleterious role of opioids on tissue regeneration through the control of ROS production in vertebrates and thus questions about opioid-based analgesia in perioperative care.