Deletion of arrestin-3 does not alter compulsive morphine-seeking behavior in an oral operant self-administration paradigm

Abstract

ABSTRACTOpioid drugs are potent analgesics that mimic the endogenous opioid peptides, endorphins and enkephalins, by activating the µ-opioid receptor. Opioid use is limited by side effects, including significant risk of opioid use disorder. Improvement of the effect/side effect profile of opioid medications is a key pursuit of opioid research, yet there is no consensus on how to achieve this goal. One hypothesis is that the degree of arrestin-3 recruitment to the µ-opioid receptor impacts therapeutic utility. However, it is not clear whether increased or decreased engagement of the µ-opioid receptor with arrestin-3 would reduce compulsive drug seeking. To examine this question, we utilized three genotypes of mice with varying abilities to recruit arrestin-3 in response to morphine in a novel longitudinal operant self-administration model. We demonstrate that drug-seeking behavior in arrestin-3 knockout and wild type mice are indistinguishable. In contrast, in mice where the µ-opioid receptor strongly recruits arrestin-3, drug-seeking behavior is reduced. Our data suggest that opioids that engage both G protein and arrestin-3, recapitulating the endogenous signaling pattern, will reduce abuse liability.