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 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 Web of Science (64) Citing Articles via Google Scholar Google Scholar Articles by Bohn, L. M. Articles by Caron, M. G. Search for Related Content PubMed PubMed Citation Articles by Bohn, L. M. Articles by Caron, M. G.

 Previous Article  |  Next Article 

The Journal of Neuroscience, December 1, 2002, 22(23):10494-10500

Differential Mechanisms of Morphine Antinociceptive Tolerance Revealed in Arrestin-2 Knock-Out Mice

Laura M. Bohn¹, Robert J. Lefkowitz², and Marc G. Caron¹

Howard Hughes Medical Institute Laboratories, Departments of ¹ Cell Biology and ² Biochemistry and Medicine, Duke University Medical Center, Durham, North Carolina 27710

Morphine induces antinociception by activating µ opioid receptors (µORs) in spinal and supraspinal regions of the CNS. arrestin-2 (arr2), a G-protein-coupled receptor-regulating protein, regulates the µOR in vivo. We have shown previously that mice lacking arr2 experience enhanced morphine-induced analgesia and do not become tolerant to morphine as determined in the hot-plate test, a paradigm that primarily assesses supraspinal pain responsiveness. To determine the general applicability of the arr2-µOR interaction in other neuronal systems, we have, in the present study, tested arr2 knock-out (arr2-KO) mice using the warm water tail-immersion paradigm, which primarily assesses spinal reflexes to painful thermal stimuli. In this test, the arr2-KO mice have greater basal nociceptive thresholds and markedly enhanced sensitivity to morphine. Interestingly, however, after a delayed onset, they do ultimately develop morphine tolerance, although to a lesser degree than the wild-type (WT) controls. In the arr2-KO but not WT mice, morphine tolerance can be completely reversed with a low dose of the classical protein kinase C (PKC) inhibitor chelerythrine. These findings provide in vivo evidence that the µOR is differentially regulated in diverse regions of the CNS. Furthermore, although arr2 appears to be the most prominent and proximal determinant of µOR desensitization and morphine tolerance, in the absence of this mechanism, the contributions of a PKC-dependent regulatory system become readily apparent.

Key words: morphine; µ opioid receptor; MOP; knock-out mice; arrestin; desensitization; G-protein-coupled receptors; tolerance; antinociception

---

Copyright © 2002 Society for Neuroscience  0270-6474/02/222310494-07$05.00/0

This article has been cited by other articles:

				V. C. Dang, I. A. Napier, and M. J. Christie Two Distinct Mechanisms Mediate Acute {micro}-Opioid Receptor Desensitization in Native Neurons J. Neurosci., March 11, 2009; 29(10): 3322 - 3327. [Abstract] [Full Text] [PDF]

				V. Labrie, S. Duffy, W. Wang, S. W. Barger, G. B. Baker, and J. C. Roder Genetic inactivation of D-amino acid oxidase enhances extinction and reversal learning in mice Learn. Mem., December 30, 2008; 16(1): 28 - 37. [Abstract] [Full Text] [PDF]

				J. L. Mathews, A. V. Smrcka, and J. M. Bidlack A Novel G{beta}{gamma}-Subunit Inhibitor Selectively Modulates {micro}-Opioid-Dependent Antinociception and Attenuates Acute Morphine-Induced Antinociceptive Tolerance and Dependence J. Neurosci., November 19, 2008; 28(47): 12183 - 12189. [Abstract] [Full Text] [PDF]

				C. L. Schmid, K. M. Raehal, and L. M. Bohn From the Cover: Agonist-directed signaling of the serotonin 2A receptor depends on {beta}-arrestin-2 interactions in vivo PNAS, January 22, 2008; 105(3): 1079 - 1084. [Abstract] [Full Text] [PDF]

				H. Zheng, H. H. Loh, and P.-Y. Law -Arrestin-Dependent {micro}-Opioid Receptor-Activated Extracellular Signal-Regulated Kinases (ERKs) Translocate to Nucleus in Contrast to G Protein-Dependent ERK Activation Mol. Pharmacol., January 1, 2008; 73(1): 178 - 190. [Abstract] [Full Text] [PDF]

				Z.-Q. Zhao, Y.-J. Gao, Y.-G. Sun, C.-S. Zhao, R. W. Gereau IV, and Z.-F. Chen Central serotonergic neurons are differentially required for opioid analgesia but not for morphine tolerance or morphine reward PNAS, September 4, 2007; 104(36): 14519 - 14524. [Abstract] [Full Text] [PDF]

				V. Fernandez-Duenas, O. Pol, P. Garcia-Nogales, L. Hernandez, E. Planas, and M. M. Puig Tolerance to the Antinociceptive and Antiexudative Effects of Morphine in a Murine Model of Peripheral Inflammation J. Pharmacol. Exp. Ther., July 1, 2007; 322(1): 360 - 368. [Abstract] [Full Text] [PDF]

				K. A. Berg, A. M. Patwardhan, T. A. Sanchez, Y. M. Silva, K. M. Hargreaves, and W. P. Clarke Rapid Modulation of {micro}-Opioid Receptor Signaling in Primary Sensory Neurons J. Pharmacol. Exp. Ther., June 1, 2007; 321(3): 839 - 847. [Abstract] [Full Text] [PDF]

				W. Walwyn, C. J. Evans, and T. G. Hales {beta}-Arrestin2 and c-Src Regulate the Constitutive Activity and Recycling of {micro} Opioid Receptors in Dorsal Root Ganglion Neurons J. Neurosci., May 9, 2007; 27(19): 5092 - 5104. [Abstract] [Full Text] [PDF]

				C. E. Groer, K. Tidgewell, R. A. Moyer, W. W. Harding, R. B. Rothman, T. E. Prisinzano, and L. M. Bohn An Opioid Agonist that Does Not Induce {micro}-Opioid Receptor--Arrestin Interactions or Receptor Internalization Mol. Pharmacol., February 1, 2007; 71(2): 549 - 557. [Abstract] [Full Text] [PDF]

				S. Li, M. L. Lee, M. R. Bruchas, G. C. Chan, D. R. Storm, and C. Chavkin Calmodulin-Stimulated Adenylyl Cyclase Gene Deletion Affects Morphine Responses Mol. Pharmacol., November 1, 2006; 70(5): 1742 - 1749. [Abstract] [Full Text] [PDF]

				A. Puckerin, L. Liu, N. Permaul, P. Carman, J. Lee, and M. A. Diverse-Pierluissi Arrestin Is Required for Agonist-induced Trafficking of Voltage-dependent Calcium Channels J. Biol. Chem., October 13, 2006; 281(41): 31131 - 31141. [Abstract] [Full Text] [PDF]

				K. M. Raehal, J. K. L. Walker, and L. M. Bohn Morphine Side Effects in {beta}-Arrestin 2 Knockout Mice J. Pharmacol. Exp. Ther., September 1, 2005; 314(3): 1195 - 1201. [Abstract] [Full Text] [PDF]

				Z. Zuo The Role of Opioid Receptor Internalization and {beta}-Arrestins in the Development of Opioid Tolerance Anesth. Analg., September 1, 2005; 101(3): 728 - 734. [Abstract] [Full Text] [PDF]

				M. J. Clark and J. R. Traynor Endogenous Regulator of G Protein Signaling Proteins Reduce {micro}-Opioid Receptor Desensitization and Down-Regulation and Adenylyl Cyclase Tolerance in C6 Cells J. Pharmacol. Exp. Ther., February 1, 2005; 312(2): 809 - 815. [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]

				V. C. Dang and J. T. Williams Chronic Morphine Treatment Reduces Recovery from Opioid Desensitization J. Neurosci., September 1, 2004; 24(35): 7699 - 7706. [Abstract] [Full Text] [PDF]

				I. Tegeder and G. Geisslinger Opioids As Modulators of Cell Death and Survival--Unraveling Mechanisms and Revealing New Indications Pharmacol. Rev., September 1, 2004; 56(3): 351 - 369. [Abstract] [Full Text] [PDF]

				L. M. Bohn, L. A. Dykstra, R. J. Lefkowitz, M. G. Caron, and L. S. Barak Relative Opioid Efficacy Is Determined by the Complements of the G Protein-Coupled Receptor Desensitization Machinery Mol. Pharmacol., July 1, 2004; 66(1): 106 - 112. [Abstract] [Full Text] [PDF]

				B. M. Cox and A. T. Crowder Receptor Domains Regulating {micro} Opioid Receptor Uncoupling and Internalization: Relevance to Opioid Tolerance Mol. Pharmacol., March 1, 2004; 65(3): 492 - 495. [Full Text] [PDF]

				J. Celver, M. Xu, W. Jin, J. Lowe, and C. Chavkin Distinct Domains of the {micro}-Opioid Receptor Control Uncoupling and Internalization Mol. Pharmacol., March 1, 2004; 65(3): 528 - 537. [Abstract] [Full Text] [PDF]

				G. B. Bolger, A. McCahill, E. Huston, Y.-F. Cheung, T. McSorley, G. S. Baillie, and M. D. Houslay The Unique Amino-terminal Region of the PDE4D5 cAMP Phosphodiesterase Isoform Confers Preferential Interaction with {beta}-Arrestins J. Biol. Chem., December 5, 2003; 278(49): 49230 - 49238. [Abstract] [Full Text] [PDF]

				L. M. Bohn, R. R. Gainetdinov, T. D. Sotnikova, I. O. Medvedev, R. J. Lefkowitz, L. A. Dykstra, and M. G. Caron Enhanced Rewarding Properties of Morphine, but not Cocaine, in {beta}arrestin-2 Knock-Out Mice J. Neurosci., November 12, 2003; 23(32): 10265 - 10273. [Abstract] [Full Text] [PDF]

				C. D. Mandyam, D. R. Thakker, and K. M. Standifer {micro}-Opioid-Induced Desensitization of Opioid Receptor-Like 1 and {micro}-Opioid Receptors: Differential Intracellular Signaling Determines Receptor Sensitivity J. Pharmacol. Exp. Ther., September 1, 2003; 306(3): 965 - 972. [Abstract] [Full Text] [PDF]

				S. L. Borgland, M. Connor, P. B. Osborne, J. B. Furness, and M. J. Christie Opioid Agonists Have Different Efficacy Profiles for G Protein Activation, Rapid Desensitization, and Endocytosis of Mu-opioid Receptors J. Biol. Chem., May 23, 2003; 278(21): 18776 - 18784. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help