Protein kinase C-mediated inhibition of μ-opioid receptor internalization and its involvement in the development of acute tolerance to peripheral μ-agonist analgesia

H. Ueda, Makoto Inoue, T. Matsumoto

Research output: Contribution to journalArticle

Abstract

We investigated the role of protein kinase C (PKC) in cell μ-opioid receptor (MOR) internalization and MOR-mediated acute tolerance in vivo. When Chinese hamster ovary cells expressing MOR were exposed to [D-Ala2,MePhe4,Gly-ol5]-enkephalin (DAMGO), receptor internalization was observed at 30 min. Incubation with morphine failed to induce receptor internalization. When calphostin C, a PKC inhibitor, was added, receptor internalization was observed as early as 10 min after morphine stimulation. The MOR internalization induced by DAMGO or morphine in the presence of calphostin C was dynamin dependent, because it was abolished 2 d after pretreatment with recombinant adenovirus to express a dominant interfering dynamin mutant (K44A/dynamin adenovirus). On the other hand, in a peripheral nociception test in mice, the nociceptive flexor response after intraplantar injection (i.pl.) of bradykinin was markedly inhibited by DAMGO (i.pl.). DAMGO analgesia was not affected by 2 hr prior injection (i.pl.) of DAMGO. Marked acute tolerance was observed after pretreatment with dynamin antisense oligodeoxynucleotide or K44A/dynamin adenovirus. The DAMGO-induced acute tolerance under such pretreatments was inhibited by calphostin C. Together, these findings suggest that PKC desensitizes MOR or has a role in the development of acute tolerance through MOR by inhibiting internalization mechanisms as a resensitization process.

Original languageEnglish (US)
Pages (from-to)2967-2973
Number of pages7
JournalJournal of Neuroscience
Volume21
Issue number9
StatePublished - May 1 2001
Externally publishedYes

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Keywords

  • Dynamin
  • Internalization
  • K44A/dynamin adenovirus
  • Peripheral acute tolerance
  • Protein kinase C
  • μ-opioid receptor

ASJC Scopus subject areas

  • Neuroscience(all)

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