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Tolerance and cross-tolerance to the antinociceptive effects of oxycodone and the imidazoline I2 receptor agonist phenyzoline in adult male rats

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Abstract

Rationale

Emerging evidence suggests the potential utility of combining opioids with imidazoline I2 receptor agonists for chronic pain. However, chronic pain management requires prolonged pharmacotherapy, and the consequence of such combination therapy remains unclear.

Objective

This study examined the anti-hyperalgesic effect of the opioid oxycodone, the selective I2 receptor agonist phenyzoline, alone and in combination, during prolonged treatment.

Methods

Von Frey filament test was used to examine the anti-hyperalgesic effect of drugs in complete Freund’s adjuvant (CFA)-induced inflammatory pain or chronic constriction injury (CCI)-induced neuropathic pain in rats. Twice-daily treatment with oxycodone and phenyzoline, alone or in combination, was continued until the development of significant tolerance (oxycodone) or as long as 19 days passed (phenyzoline).

Results

In rats receiving CFA or CCI manipulation, mechanical hyperalgesia was dose-dependently reversed by oxycodone and phenyzoline. Twice-daily treatment with 2 × ED50 dose of oxycodone for 7 days led to significant antinociceptive tolerance to oxycodone but not cross-tolerance to phenyzoline. Similarly, twice-daily treatment with 2 × ED50 dose of phenyzoline for 19 days led to significant antinociceptive tolerance to phenyzoline but not cross-tolerance to oxycodone. Twice-daily treatment with the combined oxycodone and phenyzoline using different ratios (1:3, 1:1 and 3: 1) at the doses that were functionally equivalent to the treatment doses of oxycodone and phenyzoline for 13–19 days generally led to delayed antinociceptive tolerance.

Conclusions

Combination therapy with oxycodone and I2 receptor agonists maintains prolonged antinociceptive effectiveness with reduced propensity to develop tolerance.

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Acknowledgements

This work was supported by the National Institute on Drug Abuse of the National Institutes of Health (Award no. R01DA034806) and by a grant from National Natural Science Foundation of China (81373390). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, University at Buffalo, Buffalo, NY, USA

    David A. Thorn & Jun-Xu Li

  2. Research Triangle Institute, Research Triangle Park, NC, USA

    Yanan Zhang

  3. Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NC, USA

    Jun-Xu Li

Authors
  1. David A. Thorn
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  2. Yanan Zhang
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  3. Jun-Xu Li
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Corresponding author

Correspondence to Jun-Xu Li.

Ethics declarations

Animals were maintained, and experiments were conducted in accordance with guidelines of the International Association for the Study of Pain (Zimmermann 1983) and were approved by the Institutional Animal Care and Use Committee, University at Buffalo, the State University of New York, and with the 2011 Guide for the Care and Use of Laboratory Animals (Institute of Laboratory Animal Resources on Life Sciences, National Research Council, National Academy of Sciences, Washington DC).

Conflicts of interest

The authors declare that they have no conflicts of interest.

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Thorn, D.A., Zhang, Y. & Li, JX. Tolerance and cross-tolerance to the antinociceptive effects of oxycodone and the imidazoline I2 receptor agonist phenyzoline in adult male rats. Psychopharmacology 234, 1871–1880 (2017). https://doi.org/10.1007/s00213-017-4599-4

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  • DOI: https://doi.org/10.1007/s00213-017-4599-4

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