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Article

  • The EMBO Journal (2004) 23, 3282 - 3289
  • doi:10.1038/sj.emboj.7600334

Published online: 22 July 2004

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

Stefan Schulz, Dana Mayer, Manuela Pfeiffer, Ralf Stumm, Thomas Koch and Volker Höllt

  1. Institut für Pharmakologie und Toxikologie, Otto-von-Guericke-Universität, Magdeburg, Germany

Correspondence to:

Stefan Schulz, Department of Pharmacology, Institut für Pharmakologie und Toxikologie, Otto-von-Guericke-Universität, Leipziger Strasse 44, 39120 Magdeburg, Germany. Tel.: +49 391 6715 881; Fax: +49 391 6715 869; E-mail: stefan.schulz@medizin.uni-magdeburg.de

Received 27 February 2004; Accepted 24 June 2004

Morphine is a poor inducer of mu-opioid receptor (MOR) internalization, but a potent inducer of cellular tolerance. Here we show that, in contrast to full agonists such as [D-Ala2-MePhe4-Gly-ol]enkephalin (DAMGO), morphine stimulated a selective phosphorylation of the carboxy-terminal residue 375 (Ser375). Ser375 phosphorylation was sufficient and required for morphine-induced desensitization of MOR. In the presence of full agonists, morphine revealed partial agonistic properties and potently inhibited MOR phosphorylation and internalization. Upon removal of the drug, DAMGO-desensitized receptors were rapidly dephosphorylated. In contrast, morphine-desensitized receptors remained at the plasma membrane in a Ser375-phosphorylated state for prolonged periods. Thus, morphine promotes terminal MOR desensitization by inducing a persistent modification of Ser375.

  • Keywords:

    • desensitization,
    • morphine,
    • opioid receptor,
    • phosphorylation,
    • tolerance