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The Journal of Neuroscience, September 1, 2004, 24(35):7699-7706; doi:10.1523/JNEUROSCI.2499-04.2004

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Behavioral/Systems/Cognitive
Chronic Morphine Treatment Reduces Recovery from Opioid Desensitization

Vu C. Dang and John T. Williams

Vollum Institute and Department of Physiology and Pharmacology, Oregon Health Sciences University, Portland, Oregon 97239

Tolerance and dependence result from long-term exposure to opioids, and there is growing evidence linking acute receptor desensitization to these more long-term processes. Receptor desensitization encompasses a series of events leading to the loss of receptor function and internalization. This study examines the onset and recovery from desensitization in locus ceruleus neurons recorded in brain slices taken from animals that have been chronically treated with morphine. After chronic morphine treatment, desensitization was altered as follows. First, the rate of desensitization was increased. Second, recovery from desensitization was always incomplete, even after a brief (1-2 min) exposure to agonist. This contrasts with experiments in controls in which recovery from desensitization, after a brief exposure to agonist, was complete within 25 min. Finally, morphine-6--D-glucuronide, a metabolite of morphine that was ineffective at causing desensitization in controls, induced significant desensitization in slices from morphine-treated animals. When brain slices from controls were treated with inhibitors of PKC or monensin, agents known to compromise G-protein-coupled receptor resensitization, desensitization was increased, and recovery was significantly reduced. These results indicate that receptor resensitization maintains signaling during periods of intense and sustained stimulation. After chronic morphine treatment, desensitization is potentiated, and receptor resensitization is compromised.

Key words: locus ceruleus; slices; µ-opioid receptor; electrophysiology; intracellular recording; tolerance

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Received Dec 4, 2003; revised July 6, 2004; accepted July 7, 2004.

This article has been cited by other articles:

				M. S. Virk and J. T. Williams Agonist-Specific Regulation of {micro}-Opioid Receptor Desensitization and Recovery from Desensitization Mol. Pharmacol., April 1, 2008; 73(4): 1301 - 1308. [Abstract] [Full Text] [PDF]

				D. Liao, O. O. Grigoriants, H. H. Loh, and P.-Y. Law Agonist-Dependent Postsynaptic Effects of Opioids on Miniature Excitatory Postsynaptic Currents in Cultured Hippocampal Neurons J Neurophysiol, February 1, 2007; 97(2): 1485 - 1494. [Abstract] [Full Text] [PDF]

				S. Arttamangkul, M. Torrecilla, K. Kobayashi, H. Okano, and J. T. Williams Separation of {micro}-Opioid Receptor Desensitization and Internalization: Endogenous Receptors in Primary Neuronal Cultures J. Neurosci., April 12, 2006; 26(15): 4118 - 4125. [Abstract] [Full Text] [PDF]

				V. C. Dang and J. T. Williams Morphine-Induced {micro}-Opioid Receptor Desensitization Mol. Pharmacol., October 1, 2005; 68(4): 1127 - 1132. [Abstract] [Full Text] [PDF]

				C. P. Bailey, E. Kelly, and G. Henderson Protein Kinase C Activation Enhances Morphine-Induced Rapid Desensitization of {micro}-Opioid Receptors in Mature Rat Locus Ceruleus Neurons Mol. Pharmacol., December 1, 2004; 66(6): 1592 - 1598. [Abstract] [Full Text] [PDF]

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