Does Astrocyte Elevated Gene-1 (AEG-1), a Novel Transcriptional Regulator, Mediate an Anti-opioid System?

About This Grant

Summary Adequate management of pain is an unmet medical need. Opioid analgesics that act on the μ-opioid receptor remain important pain medications but their use in chronic pain have substantial liabilities and has contributed to what is now referred to as the “opioid epidemic”. A large body of evidence suggest that activation of MOR by opioids triggers distinct signaling events that differentially control various pharmacological responses. As a result, identification of molecules or mechanisms that control MOR signaling remains critical and could provide new targets for increasing the efficacy and safety of opioid analgesics. This proposal focuses on a new protein, Astrocyte Elevated Gene-1 (AEG-1), as a possible endogenous anti-opioid regulator. We hypothesize that AEG-1 plays an important role in regulating morphine antinociceptive properties via peripheral neuronal sensory neuroinflammatory mechanisms without altering morphine reward and dependence. We will interrogate our hypothesis using the following specific aims. In Aim 1, we will identify the molecular and cellular mechanisms by which the deletion of AEG-1 reverses morphine antinociceptive tolerance. In Aim 2, we will evaluate the impact of AEG-1 deletion on morphine reward and dependence. The results of these studies will facilitate designing potential AEG-1-inhibitory strategies to increase safety and efficacy of opioid analgesic pharmacotherapy.