Role of mu opioid receptor endocytosis in the beneficial and side‐effects of prolonged opioid use

Abstract

The utility of morphine for chronic pain is hindered by the development of analgesic tolerance and dependence. For decades the field has hypothesized that tolerance is mediated by “desensitization” of opioid receptors. In fact, morphine and its derivatives are unique agonists because they do not promote endocytosis of their target receptor, the mu opioid receptor (MOR) while, paradoxically, the endogenous ligands do. In light of this, we propose that endocytosis and recycling serves a protective role in reducing opioid tolerance and dependence. To examine this hypothesis, we generated a knock‐in mouse that expresses a mutant form of the MOR, RMOR for recycling MOR, that endocytoses and recycles in response to morphine. Mice expressing RMOR show enhanced analgesia and reward to morphine compared to wild type (WT) mice and equivalent analgesia and reward to drugs that drive endocytosis in both genotypes. Importantly, mice expressing RMOR develop reduced tolerance and physical dependence to morphine, and do not transition to compulsive drug seeking even after weeks of voluntary morphine consumption, unlike WT mice. Together, these results suggest that drugs that drive endocytosis of the MOR would retain the beneficial effects of opiates including analgesia and reward, while reducing the liability for the side effects of tolerance, dependence and addiction. Supported by DA019958 and the State of California/UCSF.