| First Author | Kliewer A | Year | 2019 |
| Journal | Nat Commun | Volume | 10 |
| Issue | 1 | Pages | 367 |
| PubMed ID | 30664663 | Mgi Jnum | J:270184 |
| Mgi Id | MGI:6277309 | Doi | 10.1038/s41467-018-08162-1 |
| Citation | Kliewer A, et al. (2019) Phosphorylation-deficient G-protein-biased mu-opioid receptors improve analgesia and diminish tolerance but worsen opioid side effects. Nat Commun 10(1):367 |
| abstractText | Opioid analgesics are powerful pain relievers; however, over time, pain control diminishes as analgesic tolerance develops. The molecular mechanisms initiating tolerance have remained unresolved to date. We have previously shown that desensitization of the mu-opioid receptor and interaction with beta-arrestins is controlled by carboxyl-terminal phosphorylation. Here we created knockin mice with a series of serine- and threonine-to-alanine mutations that render the receptor increasingly unable to recruit beta-arrestins. Desensitization is inhibited in locus coeruleus neurons of mutant mice. Opioid-induced analgesia is strongly enhanced and analgesic tolerance is greatly diminished. Surprisingly, respiratory depression, constipation, and opioid withdrawal signs are unchanged or exacerbated, indicating that beta-arrestin recruitment does not contribute to the severity of opioid side effects and, hence, predicting that G-protein-biased micro-agonists are still likely to elicit severe adverse effects. In conclusion, our findings identify carboxyl-terminal multisite phosphorylation as key step that drives acute mu-opioid receptor desensitization and long-term tolerance. |
