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

Citation
H. Ueda et al., Protein kinase C-mediated inhibition of mu-opioid receptor internalizationand its involvement in the development of acute tolerance to peripheral mu-agonist analgesia, J NEUROSC, 21(9), 2001, pp. 2967-2973
Citations number
54
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Neurosciences & Behavoir
Journal title
JOURNAL OF NEUROSCIENCE
ISSN journal
0270-6474 → ACNP
Volume
21
Issue
9
Year of publication
2001
Pages
2967 - 2973
Database
ISI
SICI code
0270-6474(20010501)21:9<2967:PKCIOM>2.0.ZU;2-A
Abstract
We investigated the role of protein kinase C (PKC) in cell mu -opioid recep tor (MOR) internalization and MOR-mediated acute tolerance in vivo. When Ch inese hamster ovary cells expressing MOR were exposed to [D-Ala(2),MePhe(4) ,Gly-ol(5)]enkephalin (DAMGO), receptor internalization was observed at 30 min. Incubation with morphine failed to induce receptor internalization. Wh en calphostin C, a PKC inhibitor, was added, receptor internalization was o bserved as early as 10 min after morphine stimulation. The MOR internalizat ion induced by DAMGO or morphine in the presence of calphostin C was dynami n dependent, because it was abolished 2 d after pretreatment with recombina nt adenovirus to express a dominant interfering dynamin mutant (K44A/dynami n adenovirus). On the other hand, in a peripheral nociception test in mice, the nociceptive flexor response after intraplantar injection (i.pl.) of br adykinin was markedly inhibited by DAMGO (i.pl.). DAMGO analgesia was not a ffected by 2 hr prior injection (i.pl.) of DAMGO. Marked acute tolerance wa s observed after pretreatment with dynamin antisense oligodeoxynucleotide o r K44A/dynamin adenovirus. The DAMGO-induced acute tolerance under such pre treatments was inhibited by calphostin C. Together, these findings suggest that PKC desensitizes MOR or has a role in the development of acute toleran ce through MOR by inhibiting internalization mechanisms as a resensitizatio n process.