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Research ArticleArticle

Receptor Endocytosis Counteracts the Development of Opioid Tolerance

Thomas Koch, Antje Widera, Katharina Bartzsch, Stefan Schulz, Lars-Ove Brandenburg, Nicole Wundrack, Andrea Beyer, Gisela Grecksch and Volker Höllt
Molecular Pharmacology January 2005, 67 (1) 280-287; DOI: https://doi.org/10.1124/mol.104.004994
Thomas Koch
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Antje Widera
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Katharina Bartzsch
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Stefan Schulz
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Lars-Ove Brandenburg
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Nicole Wundrack
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Andrea Beyer
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Gisela Grecksch
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Volker Höllt
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Abstract

In contrast to endogenous opioids, the highly addictive drug morphine activates the μ-opioid receptor without causing its rapid endocytosis. It has recently been reported that coapplication of low concentrations of [d-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (DAMGO) facilitates the ability of morphine to stimulate μ-opioid receptor endocytosis and prevents the development of morphine tolerance in rats. To investigate the clinical relevance of this finding for analgesic therapy, the endocytotic efficacies of a series of clinically used opioids were determined, and the effect of a combination of these drugs with morphine on the μ-opioid receptor endocytosis in receptor-expressing human embryonic kidney (HEK) 293 cells was quantified. The combination of morphine and opioid drugs with high endocytotic efficacies (e.g., DAMGO, etonitazene, sufentanil, β-endorphin, piritramide, or methadone) did not result in a facilitation of morphine-mediated endocytosis but rather in a decrease of the receptor endocytosis mediated by the tested opioid drugs. These findings demonstrate a partial agonistic effect of morphine on the agonist-induced receptor endocytosis. Moreover, we demonstrated that the endocytotic potencies of opioid drugs are negatively correlated with their ability to cause receptor desensitization and opioid tolerance in HEK 293 cells. These results strongly support the hypothesis that μ-opioid receptor endocytosis counteracts receptor desensitization and opioid tolerance by inducing fast receptor reactivation and recycling. In addition, it is shown that agonist-induced receptor endocytosis facilitates the compensatory up-regulation of the cAMP pathway, a cellular hallmark of opioid withdrawal. Our findings suggest that opioids with high endocytotic efficacies might cause reduced opioid tolerance but can facilitate compensatory mechanisms, resulting in an enhanced opioid dependence.

  • Received July 14, 2004.
  • Accepted October 8, 2004.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 67 (1)
Molecular Pharmacology
Vol. 67, Issue 1
1 Jan 2005
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Research ArticleArticle

Receptor Endocytosis Counteracts the Development of Opioid Tolerance

Thomas Koch, Antje Widera, Katharina Bartzsch, Stefan Schulz, Lars-Ove Brandenburg, Nicole Wundrack, Andrea Beyer, Gisela Grecksch and Volker Höllt
Molecular Pharmacology January 1, 2005, 67 (1) 280-287; DOI: https://doi.org/10.1124/mol.104.004994

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Research ArticleArticle

Receptor Endocytosis Counteracts the Development of Opioid Tolerance

Thomas Koch, Antje Widera, Katharina Bartzsch, Stefan Schulz, Lars-Ove Brandenburg, Nicole Wundrack, Andrea Beyer, Gisela Grecksch and Volker Höllt
Molecular Pharmacology January 1, 2005, 67 (1) 280-287; DOI: https://doi.org/10.1124/mol.104.004994
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