The role of mu-opioid receptor (MOR) downregulation in opioid tolerance remains controversial. Here we used a novel knock-in mouse to examine how changing the extent of MOR downregulation alters the development of morphine tolerance. These mice express a mutant MOR, DMOR, that differs from the wild-type (WT) MOR in two ways: 1) Unlike the recycling WT MOR, the mutant DMOR is targeted for degradation following its internalization, thus facilitating downregulation and 2) unlike the WT MOR, DMOR is efficiently internalized in response to morphine activation. We found that both WT MOR and DMOR mice develop tolerance to morphine, but DMOR mice exhibit a more rapid onset of tolerance and show receptor downregulation. WT MOR mice develop morphine tolerance more slowly, but even once profoundly tolerant, show no receptor downregulation. Furthermore, WT show significantly more morphine dependence after chronic treatment indicated by withdrawal than DMOR mice. Together these data indicate that tolerance mediated by receptor downregulation manifests differently both at the behavioral and biochemical level than does the actual morphine tolerance that occurs in WT mice. Thus together, these data indicate that loss of receptor function is not a major contributor to morphine tolerance in WT MOR mice.
- Received January 24, 2011.
- Revision received May 3, 2011.
- Accepted May 4, 2011.
- The American Society for Pharmacology and Experimental Therapeutics