Does the Mu-Delta Opioid Receptor Heterodimer Repress Akt Kinase to Reduce Opioid Anti-Nociception?

The mu opioid receptor (MOR) and delta opioid receptor (DOR) have been shown to interact in the regulation of pain, opioid side effects, and similar physiology. However, the mechanism of this interaction is still unknown. Limited in vitro and in vivo experiments have suggested that these receptors heterodimerize (MDOR) to regulate pain and opioid response. However, in vivo studies of this receptor complex are very challenging due to the lack of selective tools to study MDOR activity. We thus designed a first‐in‐class MDOR‐selective antagonist named D24M. Using this tool, we found striking evidence suggesting that the MDOR acts as a negative feedback loop, blocking analgesia while enhancing side effects. We performed phosphoproteomic analysis of D24M and/or oxymorphone‐treated CD‐1 mouse brainstems, and found a network of signaling molecules possibly implicated in MDOR function. Among these altered molecules, we found evidence that the kinase Akt was repressed by oxymorphone treatment and restored by D24M co‐treatment, suggesting that Akt repression may be downstream of the MDOR in vivo , and responsible for the blockade of opioid analgesia by this heterodimer. We tested this hypothesis in male and female CD‐1 mice by intracerebroventricular injection of combinations of oxymorphone, D24M, and the selective Akt inhibitor Akt‐i. We found that D24M increased Oxymorphone‐induced anti‐nociception compared to Oxymorphone alone in the tail flick assay, as in our previous studies. We also found that Akt‐i co‐treatment blocked the increase in anti‐nociception caused by D24M in male, but not female mice. These results suggest that Akt may be repressed in a sex‐specific manner by the MDOR to repress opioid anti‐nociception as part of an anti‐opioid negative feedback loop. These results also suggest that MDOR‐selective antagonists could be novel therapeutics to enhance opioid efficacy while decreasing side effects. Support or Funding Information Funding Information These studies were funded by NIH R21DA044509 and UG3DA047717 to JMS. The authors have no relevant conflicts of interest to declare.