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The Journal of Neuroscience, May 1, 2001, 21(9):2967-2973

Protein Kinase C-Mediated Inhibition of µ-Opioid Receptor Internalization and Its Involvement in the Development of Acute Tolerance to Peripheral µ-Agonist Analgesia

Hiroshi Ueda, Makoto Inoue, and Takayuki Matsumoto

Department of Molecular Pharmacology and Neuroscience, Nagasaki University School of Pharmaceutical Sciences, Nagasaki 852-8521, Japan

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.

Key words: protein kinase C; peripheral acute tolerance; internalization; µ-opioid receptor; dynamin; K44A/dynamin adenovirus

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Copyright © 2001 Society for Neuroscience  0270-6474/01/2192967-07$05.00/0

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