Abstract
Repeated administration of morphine is associated with the development of tolerance, yet the mechanism underlying this phenomenon is still poorly understood. Recent evidence implicating glycogen synthase kinase 3 (GSK3) in opioid receptor signaling pathways has prompted us to investigate its role in morphine tolerance. Administration of 10 mg/kg morphine i.p. to Wistar rats twice daily for 8 days resulted in complete tolerance to its analgesic effects as measured by the tail-flick test. When injections of morphine were preceded by intrathecal (i.t.) administration of either an inhibitor of GSK3 [(3-(2,4-dichlorophenyl)-4-(1-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione (SB216763) or 6-bromoindirubin-3′oxime] or an inhibitor of cyclin-dependent kinase (Cdk), roscovitine, development of tolerance to morphine analgesia was completely abolished. In addition, a single i.t. injection of either kinase inhibitor was able to restore in a dose-dependent manner the analgesic effect of morphine in morphine-tolerant rats. None of the inhibitors in doses used in the present study had analgesic effects of their own nor an effect on the analgesic potency of morphine. Repeated i.t. administration of either inhibitor had caused an increase in abundance of GSK-3β phosphorylated at Ser9 in the dorsal lumbar part of the spinal cord of rats that were chronically treated with morphine. Furthermore, reversal of morphine tolerance by a single injection of either inhibitor was always associated with increased abundance of phospho-GSK3β. In conclusion, our data indicate that chronic morphine treatment activates a highly efficient pathway by means of which Cdk5 regulates GSK3β activity.
Footnotes
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This research was supported by statutory funds (BP) by Grant PBZ-KBN-033/P05/2000 (to J.R.P., I.O., A.W.B., and R.P.) from the Ministry of Scientific Research and Information Technology (Warsaw, Poland) and partially by European Union Grant GENADDICT LSHM-CT-2004-005166 (to W.M.). I.O. received a contribution from the Foundation for Polish Science.
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J.R.P. and I.O. contributed equally to this work.
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Parts of the work were presented at The 15th Annual Meeting of the European Neuropeptide Club; 2005 May 19–21; Riga, Latvia; The 11th World Congress on Pain; 2005 Aug 18–19, 2005; Sydney, Australia; and The 7th International Congress of the Polish Neuroscience Society, 2005 Sept 7–10, 2005; Kraków, Poland.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.106.107581.
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ABBREVIATIONS: GSK, glycogen synthase kinase; Cdk, cyclin-dependent kinase; DMSO, dimethyl sulfoxide; SB216763, 3-(2,4-dichlorophenyl)-4-(1-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione; roscovitine, 2-(R)-[[9-(1-methylethyl)-6-[(phenylmethyl)amino]-9H-purin-2-yl]amino]-1-butanol; BIO, (2′Z,3′E)-6-bromoindirubin-3′-oxime; PP1, protein phosphatase 1; DARPP-32, dopamine- and cAMP-regulated phosphoprotein of Mr 32,000; NMDA, N-methyl-d-aspartate.
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↵1 Current affiliation: Molecular Biology of the Cell I, German Cancer Research Center, Heidelberg, Germany.
- Received May 10, 2006.
- Accepted August 9, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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