Cellular tolerance at the µ-opioid receptor is phosphorylation dependent

Elife. 2018 Mar 28;7:e34989. doi: 10.7554/eLife.34989.


Phosphorylation of the μ-opioid receptor (MOR) is known as a key step in desensitization and internalization but the role in the development of long-term tolerance at the cellular level is not known. Viral expression of wild type (exWT) and mutant MORs, where all phosphorylation sites on the C-terminus (Total Phosphorylation Deficient (TPD)) were mutated to alanine, were examined in locus coeruleus neurons in a MOR knockout rat. Both receptors activated potassium conductance similar to endogenous receptors in wild type animals. The exWT receptors, like endogenous receptors, acutely desensitized, internalized and, after chronic morphine treatment, displayed signs of tolerance. However, TPD receptors did not desensitize or internalize with agonist treatment. In addition the TPD receptors did not develop cellular tolerance following chronic morphine treatment. Thus C-terminal phosphorylation is necessary for the expression of acute desensitization, trafficking and one sign of long-term tolerance to morphine at the cellular level.

Keywords: Desensitization; Locus Coeruleus; internalization; neuroscience; opioid; phosphorylation; rat; tolerance.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Gene Knockout Techniques
  • Locus Coeruleus / cytology
  • Morphine / metabolism
  • Neurons / metabolism
  • Phosphorylation
  • Potassium / metabolism
  • Protein Processing, Post-Translational*
  • Rats
  • Receptors, Opioid, mu / metabolism*


  • Receptors, Opioid, mu
  • Morphine
  • Potassium