UCSF

The biological actions of morphine and other opioid narcotics are mediated primarily by the mu opioid receptor (MOR). In response to endogenous opioids, the signaling of the MOR is regulated by a conserved endocytic mechanism, involving both the desensitization of signaling by receptor phosphorylation and arrestin recruitment and the subsequent resensitization by endocytosis and recycling. In response to morphine, however, this regulatory mechanism is only weakly engaged, resulting in persistent MOR desensitization without resensitization in some cells and in persistent MOR activation without desensitization in others. We hypothesized that this could have multiple consequences for morphine's physiological effects. First, persistent MOR desensitization, arising within minutes to days of morphine administration, could contribute to acutely diminished sensitivity to morphine and acute tolerance. Second, compensatory adaptations in response to persistent MOR activation, arising within hours to weeks of morphine administration, could contribute to chronic tolerance, physical dependence, and possibly addiction. To test this hypothesis, we generated a mutant Recycling MOR (RMOR) that desensitizes, internalizes, and recycles in response to morphine. Here, we describe the phenotype of knock-in mice expressing the mutant RMOR in place of the wild-type receptor. Consistent with our hypothesis, RMOR mice exhibited increased analgesia and reward selectively in response to morphine. Furthermore, they developed reduced tolerance and physical dependence following chronic morphine treatment, and they were less likely to progress from controlled to compulsive drug seeking when given the opportunity to freely self-administer morphine. These results suggest that promoting agonist-induced MOR desensitization and endocytosis preserves the therapeutically desirable effects of opioid drugs while preventing their negative side effects, particularly tolerance, physical dependence, and addiction.