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Research ArticleNeuropharmacology

The Role of β-Arrestin2 in the Mechanism of Morphine Tolerance in the Mouse and Guinea Pig Gastrointestinal Tract

Minho Kang, Hercules T. Maguma, Tricia H. Smith, Gracious R. Ross, William L. Dewey and Hamid I. Akbarali
Journal of Pharmacology and Experimental Therapeutics March 2012, 340 (3) 567-576; DOI: https://doi.org/10.1124/jpet.111.186320
Minho Kang
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Hercules T. Maguma
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Tricia H. Smith
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Gracious R. Ross
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William L. Dewey
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Hamid I. Akbarali
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Abstract

β-Arrestin2 has been reported to play an essential role in analgesic tolerance. Analgesic tolerance without concomitant tolerance to constipation is a limiting side effect of chronic morphine treatment. Because tolerance to morphine develops in the mouse ileum but not the colon, we therefore examined whether the role of β-arrestin2 in the mechanism of morphine tolerance differs in the ileum and colon. In both guinea pig and mouse, chronic in vitro exposure (2 h, 10 μM) to morphine resulted in tolerance development in the isolated ileum but not the colon. The IC50 values for morphine-induced inhibition of electrical field stimulation contraction of guinea pig longitudinal muscle myenteric plexus shifted rightward in the ileum from 5.7 ± 0.08 (n = 9) to 5.45 ± 0.09 (n = 6) (p < 0.001) after morphine exposure. A significant shift was not observed in the colon. Similar differential tolerance was seen between the mouse ileum and the colon. However, tolerance developed in the colon from β-arrestin2 knockout mice. β-Arrestin2 and extracellular signal-regulated kinase 1/2 expression levels were determined further by Western blot analyses in guinea pig longitudinal muscle myenteric plexus. A time-dependent decrease in the expression of β-arrestin2 and extracellular signal-regulated kinase 1/2 occurred in the ileum but not the colon after 2 h of morphine (10 μM) exposure. Naloxone prevented the decrease in β-arrestin2. In the isolated ileum from guinea pigs chronically treated in vivo with morphine for 7 days, neither additional tolerance to in vitro exposure of morphine nor a decrease in β-arrestin2 occurred. We conclude that a decrease in β-arrestin2 is associated with tolerance development to morphine in the gastrointestinal tract.

Footnotes

  • This work was supported by the National Institutes of Health National Institute on Drug Abuse [Grants R01-DA024009, T32-DA007027, P50-DA005274].

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    http://dx.doi.org/10.1124/jpet.111.186320.

  • ↵Embedded Image The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    GRK
    G protein-coupled receptor kinase
    ANOVA
    analysis of variance
    EFS
    electrical field stimulation
    ERK
    extracellular signal-regulated kinase
    GAPDH
    glyceraldehyde-3-phosphate dehydrogenase
    LMMP
    longitudinal muscle myenteric plexus
    TTX
    tetrodotoxin
    Ct
    cycle threshold.

  • Received July 22, 2011.
  • Accepted November 28, 2011.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 340 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 340, Issue 3
1 Mar 2012
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Research ArticleNeuropharmacology

β-Arrestin2 in Morphine Tolerance

Minho Kang, Hercules T. Maguma, Tricia H. Smith, Gracious R. Ross, William L. Dewey and Hamid I. Akbarali
Journal of Pharmacology and Experimental Therapeutics March 1, 2012, 340 (3) 567-576; DOI: https://doi.org/10.1124/jpet.111.186320

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Research ArticleNeuropharmacology

β-Arrestin2 in Morphine Tolerance

Minho Kang, Hercules T. Maguma, Tricia H. Smith, Gracious R. Ross, William L. Dewey and Hamid I. Akbarali
Journal of Pharmacology and Experimental Therapeutics March 1, 2012, 340 (3) 567-576; DOI: https://doi.org/10.1124/jpet.111.186320
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