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Morphine induces terminal micro-opioid receptor desensitization by sustained phosphorylation of serine-375

Stefan Schulz1, Dana Mayer, Manuela Pfeiffer

  • 1Institut für Pharmakologie und Toxikologie, Otto-von-Guericke-Universität, Magdeburg, Germany. stefan.schulz@medizin.uni-magdeburg.de

The EMBO Journal
|July 24, 2004
PubMed

Insights

Morphine poorly internalizes micro-opioid receptors (MOR) but causes tolerance. It uniquely phosphorylates Ser(375), a key step for persistent MOR desensitization and cellular tolerance.

Area of Science:

  • Pharmacology
  • Cell Biology
  • Neuroscience

Background:

  • Micro-opioid receptors (MOR) mediate pain relief but also tolerance.
  • Morphine is a weak inducer of MOR internalization compared to full agonists like DAMGO.
  • Cellular tolerance to morphine is a significant clinical challenge.

Purpose of the Study:

  • To investigate the molecular mechanisms underlying morphine's induction of cellular tolerance.
  • To compare the effects of morphine and full MOR agonists on receptor phosphorylation and internalization.
  • To identify specific receptor modifications responsible for persistent desensitization.

Main Methods:

  • Utilized cell-based assays to measure MOR phosphorylation and internalization.
  • Compared the effects of morphine and DAMGO on MOR signaling.
  • Investigated the role of specific serine residue phosphorylation (Ser(375)) in MOR desensitization.

Main Results:

  • Morphine selectively induced phosphorylation of Ser(375) on MOR, unlike DAMGO.
  • Ser(375) phosphorylation was necessary and sufficient for morphine-induced MOR desensitization.
  • Morphine inhibited MOR phosphorylation and internalization in the presence of full agonists.
  • Morphine-desensitized MOR remained phosphorylated at Ser(375) at the plasma membrane long-term.

Conclusions:

  • Morphine promotes sustained micro-opioid receptor desensitization through persistent Ser(375) phosphorylation.
  • This mechanism explains morphine's potent induction of cellular tolerance.
  • Targeting Ser(375) modification may offer strategies to manage opioid tolerance.

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