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

EMBO J. 2004 Aug 18;23(16):3282-9. doi: 10.1038/sj.emboj.7600334. Epub 2004 Jul 22.


Morphine is a poor inducer of micro-opioid receptor (MOR) internalization, but a potent inducer of cellular tolerance. Here we show that, in contrast to full agonists such as [D-Ala(2)-MePhe(4)-Gly-ol]enkephalin (DAMGO), morphine stimulated a selective phosphorylation of the carboxy-terminal residue 375 (Ser(375)). Ser(375) 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 Ser(375)-phosphorylated state for prolonged periods. Thus, morphine promotes terminal MOR desensitization by inducing a persistent modification of Ser(375).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / pharmacology
  • Humans
  • Morphine / pharmacology*
  • Mutation / genetics
  • Phosphorylation / drug effects
  • Phosphoserine / metabolism
  • Receptors, Opioid, mu / genetics
  • Receptors, Opioid, mu / metabolism*


  • Receptors, Opioid, mu
  • Enkephalin, Ala(2)-MePhe(4)-Gly(5)-
  • Phosphoserine
  • Morphine