QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

This Article Full Text Full Text (PDF) Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (32) Citing Articles via Google Scholar Google Scholar Articles by Narita, M. Articles by Tseng, L. F. Search for Related Content PubMed PubMed Citation Articles by Narita, M. Articles by Tseng, L. F.

 Previous Article  |  Next Article 

The Journal of Neuroscience, June 1, 2001, 21(11):3715-3720

Involvement of Spinal Protein Kinase C in the Attenuation of Opioid µ-Receptor-Mediated G-Protein Activation after Chronic Intrathecal Administration of [D-Ala²,N-MePhe⁴,Gly-Ol⁵]Enkephalin

Minoru Narita^{1, 2}, Hirokazu Mizoguchi², Michiko Narita², Hiroshi Nagase^{2, 3}, Tsutomu Suzuki¹, and Leon F. Tseng²

¹ Department of Toxicology, Hoshi University, School of Pharmacy, Tokyo, 142-8501, Japan, ² Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, and ³ Pharmaceutical Research Laboratories, Toray Industries Incorporated, Kamakura 248-8555, Japan

The present study was designed to investigate the role of a protein kinase C (PKC) isoform in the uncoupling of the µ-opioid receptor from G-proteins after repeated intrathecal injection of a selective µ-receptor agonist, [D-Ala²,N-MePhe⁴,Gly-ol⁵]enkephalin (DAMGO), in the spinal cord of mice. The activation of G-proteins by opioids was measured by monitoring the guanosine-5'-o-(3-[³⁵S]thio)triphosphate ([³⁵S]GTPS) binding. Mice were injected intrathecally with saline or DAMGO once a day for 1-7 d. At 24 hr after every injection the spinal cord membranes were prepared for the assay. The enhanced [³⁵S]GTPS binding by µ-agonists DAMGO, endomorphin-1, or endomorphin-2 was attenuated clearly in spinal cord membranes obtained from mice that were treated intrathecally with DAMGO for 5 and 7 d, but not for 1 or 3 d. By contrast, no change in levels of [³⁵S]GTPS binding induced by the -receptor agonist SNC-80 or -receptor agonist U-50,488H was noted in membranes obtained from mice that were treated with DAMGO. Concomitant intrathecal administration of a specific PKC inhibitor Ro-32-0432 with DAMGO blocked the attenuation of DAMGO-induced G-protein activation that was caused by chronic DAMGO treatment. Western blotting analysis showed that chronic DAMGO treatment increased the levels of PKC, but not PKC, PKCI, and PKCII isoforms, in spinal cord membranes. Furthermore, mice lacking PKC failed to exhibit the desensitization of the DAMGO-stimulated [³⁵S]GTPS binding after repeated DAMGO injection. These findings indicate that repeated intrathecal administration of DAMGO may activate the PKC isoform and in turn cause a desensitization of µ-receptor-mediated G-protein activation in the mouse spinal cord.

Key words: µ-opioid receptor; protein kinase C; phosphorylation; tolerance; G-protein; spinal cord

---

Copyright © 2001 Society for Neuroscience  0270-6474/01/21113715-06$05.00/0

This article has been cited by other articles:

				J. Mao, B. Sung, R.-R. Ji, and G. Lim Chronic Morphine Induces Downregulation of Spinal Glutamate Transporters: Implications in Morphine Tolerance and Abnormal Pain Sensitivity J. Neurosci., September 15, 2002; 22(18): 8312 - 8323. [Abstract] [Full Text] [PDF]

				J. Mao, B. Sung, R.-R. Ji, and G. Lim Neuronal Apoptosis Associated with Morphine Tolerance: Evidence for an Opioid-Induced Neurotoxic Mechanism J. Neurosci., September 1, 2002; 22(17): 7650 - 7661. [Abstract] [Full Text] [PDF]

				C. D. Mandyam, D. R. Thakker, J. L. Christensen, and K. M. Standifer Orphanin FQ/Nociceptin-Mediated Desensitization of Opioid Receptor-Like 1 Receptor and {micro} Opioid Receptors Involves Protein Kinase C: A Molecular Mechanism for Heterologous Cross-Talk J. Pharmacol. Exp. Ther., August 1, 2002; 302(2): 502 - 509. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help