Morphine‐induced mu opioid receptor trafficking enhances reward yet prevents compulsive drug use

Amy Chang Berger,Jennifer L Whistler

doi:10.1002/emmm.201100144

Abstract

Morphine, heroin and other commonly abused opioids induce little mu opioid receptor (MOR) trafficking compared to endogenous opioids. We utilized knock-in mice expressing a mutant recycling MOR (RMOR) that desensitizes and is internalized in response to morphine to show that facilitating MOR trafficking not only enhances morphine reward but, despite this, reduces the development of addiction-like behaviours. To demonstrate this, we developed a novel model of the transition from controlled to compulsive drug use that recapitulates many features of human addiction, including persistent drug seeking despite adverse consequences and a decreased preference for alternative rewards. These behaviours emerged spontaneously in wild-type but not RMOR mice, and their intensity predicted the reinstatement of morphine seeking after extended abstinence, while prior morphine intake did not. These results confirm previous findings in the rat that addiction can be dissociated from both reward and consumption. Most importantly, these results demonstrate that one can simultaneously reduce the ‘addictiveness’ of morphine and enhance its desirable effects by promoting agonist-induced MOR trafficking.

Highlights

For decades it has been a priority of opioid pharmaceutical research to develop an analgesic that can be used for extended periods of time without causing tolerance, dependence and addiction
We developed a novel model of the transition from controlled to compulsive drug use that recapitulates many features of human addiction, including persistent drug seeking despite adverse consequences and a decreased preference for alternative rewards
This demonstrates that the mutant recycling MOR (RMOR) functions equivalently to the WT receptor in response to ligands, like methadone, that promote mu opioid receptor (MOR) trafficking, and indicates that the potentiation of morphine reward in RMOR mice is due to a selective enhancement of morphine-induced trafficking and not some other non-specific gain-of-function

Summary

Introduction

For decades it has been a priority of opioid pharmaceutical research to develop an analgesic that can be used for extended periods of time without causing tolerance, dependence and addiction No such drug has yet been developed; currently available opioids, which are primarily agonists of the mu opioid receptor (MOR), a Gi/o-coupled receptor, induce varying degrees of tolerance and dependence when they are used at acutely equi-antinociceptive doses (Duttaroy & Yoburn, 1995; Grecksch et al, 2006; Kim et al, 2008; Walker & Young, 2001). Following activation by endogenous opioid peptides and the small molecule drug, methadone, the MOR is rapidly phosphorylated by GPCR kinases (GRKs) and bound by arrestins (for review, see von Zastrow, 2010). Arrestins recruit components of the endocytic machinery, and internalized MORs are subsequently resensitized by recycling back to the plasma membrane (von Zastrow, 2010)

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