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Development of tolerance and sensitization to different opioid agonists in rats

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Abstract

Rationale

Despite numerous investigations, the mechanisms underlying the development of opioid tolerance are far from clear. However, several in vitro studies implicated a protective role of agonist-induced μ-opioid receptor endocytosis in the development of opioid tolerance. Moreover, we have recently demonstrated that the high-efficacy agonist etonitazene promotes rapid endocytosis of μ-opioid receptors, whereas the agonist morphine and the low-efficacy agonist buprenorphine fail to promote detectable receptor endocytosis in μ-opioid receptor expressing HEK293 cells.

Objectives

The present study explored the effects of these opioids on the development of tolerance and sensitization in rats in vivo.

Methods

The opioid effects were quantified using the hot plate, electric tail root stimulation, and the locomotor activity chamber in male Wistar rats. Dose–response curves were generated for each test drug. To induce tolerance, equieffective doses of etonitazene, morphine, and buprenorphine were administered daily for 29 days.

Results

We found that chronic treatment with the noninternalizing drugs buprenorphine and morphine resulted in a greater development of tolerance than etonitazene. In addition, the sensitization to the locomotor stimulant effect was high after buprenorphine and morphine, but was lacking after chronic etonitazene application.

Conclusion

The results support a role for the endocytotic potency of agonists in the development of tolerance and addiction during long-term opioid treatment.

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Acknowledgements

We thank P. Dehmel and G. Schulze for their excellent technical assistance.

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Authors and Affiliations

  1. Institute of Pharmacology and Toxicology, Faculty of Medicine, Otto-von-Guericke-University Magdeburg, Leipziger Str. 44, 39120, Magdeburg, Germany

    Gisela Grecksch, Katharina Bartzsch, Antje Widera, Axel Becker, Volker Höllt & Thomas Koch

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  1. Gisela Grecksch
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  2. Katharina Bartzsch
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  3. Antje Widera
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  4. Axel Becker
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  5. Volker Höllt
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  6. Thomas Koch
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Correspondence to Gisela Grecksch.

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Grecksch, G., Bartzsch, K., Widera, A. et al. Development of tolerance and sensitization to different opioid agonists in rats. Psychopharmacology 186, 177–184 (2006). https://doi.org/10.1007/s00213-006-0365-8

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  • DOI: https://doi.org/10.1007/s00213-006-0365-8

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