Engagement of Beta-Arrestin 2 at the μ-opioid receptor reduces the abuse liability of opioids in mice during operant self-administration

Abstract

<b>Abstract ID 27678</b> <b>Poster Board 477</b> In the United States, opioid overdoses claim the lives of 254 people daily. Despite their significant risks, opioid analgesics, including morphine, codeine, Vicodin and Oxycontin, are still regarded as the gold standard for alleviating pain clinically. There is still much unknown about what cellular mechanisms could improve the safety margin of these drugs, including reducing abuse liability. All of these drugs exert their analgesic effects through activation of the G_icoupled μ- Opioid receptor (MOR). When MOR is activated by its endogenous ligand, a regulatory molecule called βeta-Arrestin-2 (βAR2) is recruited to the receptor, causing titration of signal transduction and subsequent internalization and recycling of the receptor. Conversely, when MOR is activated by many clinically relevant opioid drugs, such as morphine, it does not effectively recruit βAR2. The lack of βAR2 recruitment results in receptors remaining present on the membrane without being internalized and recycled back to the membrane. Continuous signaling from the membrane results in cAMP superactivation, a homeostatic adaptation meant to dampen the signaling. This cAMP superactivation has been implicated in neuronal and behavioral plasticity associated with compulsive drug seeking, the correlate of Opioid Use Disorders (OUDs) in mice. We hypothesize that effective recruitment of βAR2 to activated MORs will prevent cAMP superactivation, therefore preventing the neuronal and behavioral plasticity that result in compulsive drug seeking behavior. To investigate this hypothesis, this study utilizes four different genotypes of mice, with varying βAR2 recruitment profiles in response to morphine: WT(poorly recruits βAR2), RMOR (strongly recruits BAR), βAR2-KO (does not recruit βAR2), βAR2-KO/RMOR (does not recruit βAR2). We utilized a novel oral operant self-administration paradigm for 17 weeks to model the transition from impulsive to compulsive drug use. At the end of 17 weeks, operant self-administration was extinguished and reinstatement was assessed to model OUDs. We calculated a composite compulsivity score to encapsulate behavior throughout the paradigm and classify each subject as compulsive or non-compulsive. Our results show that genotypes that effectively recruit βAR2 engaged in compulsive drug seeking less. We also show that compulsive drug seeking is not dependent on the amount of opioid consumed, nor the preference for opioid over other rewards. These results imply that drugs which effectively recruit βAR2 in response to activation at MOR have therapeutic utility as analgesics with reduced abuse liability. <b>Support/Funding Information:</b> R21 DA 049565