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Research ArticleNEUROPHARMACOLOGY

Incomplete, Asymmetric, and Route-Dependent Cross-Tolerance between Oxycodone and Morphine in the Dark Agouti Rat

Carsten K. Nielsen, Fraser B. Ross and Maree T. Smith
Journal of Pharmacology and Experimental Therapeutics October 2000, 295 (1) 91-99;
Carsten K. Nielsen
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Fraser B. Ross
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Maree T. Smith
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Abstract

Our previous studies indicate that oxycodone is a putative κ-opioid agonist, whereas morphine is a well documented μ-opioid agonist. Because there is limited information regarding the development of tolerance to oxycodone, this study was designed to 1) document the development of tolerance to the antinociceptive effects of chronically infused i.v. oxycodone relative to that for i.v. morphine and 2) quantify the degree of antinociceptive cross-tolerance between morphine and oxycodone in adult male Dark Agouti (DA) rats. Antinociceptive testing was performed using the tail-flick latency test. Complete antinociceptive tolerance was achieved in 48 to 84 h after chronic infusion of equi-antinociceptive doses of i.v. oxycodone (2.5 mg/24 h and 5 mg/24 h) and i.v. morphine (10 mg/24 h and 20 mg/24 h, respectively). Dose-response curves for bolus doses of i.v. and i.c.v. morphine and oxycodone were produced in naive, morphine-tolerant, and oxycodone-tolerant rats. Consistent with our previous findings that oxycodone and morphine produce their intrinsic antinociceptive effects through distinctly different opioid receptor populations, there was no discernible cross-tolerance when i.c.v. oxycodone was given to morphine-tolerant rats. Similarly, only a low degree of cross-tolerance (≈24%) was observed after i.v. oxycodone administration to morphine-tolerant rats. By contrast, both i.v. and i.c.v. morphine showed a high degree of cross-tolerance (≈71% and ≈54%, respectively) in rats rendered tolerant to oxycodone. Taken together, these findings suggest that, after parenteral but not supraspinal administration, oxycodone is metabolized to a μ-opioid agonist metabolite, thereby explaining asymmetric and incomplete cross-tolerance between oxycodone and morphine.

Footnotes

  • Send reprint requests to: A/Prof Maree T. Smith, School of Pharmacy, The University of Queensland, St. Lucia, Queensland 4072, Australia. E-mail: m.smith{at}pharmacy.uq.edu.au

  • ↵1 Carsten K. Nielsen was supported by a University of Queensland Postgraduate Research Award, and this research was supported financially by The University of Queensland Research Grants Scheme. This research was presented in Abstract form at the 9th World Congress on Pain in Vienna (Austria) in 1999.

  • Abbreviations:
    nor-BNI
    norbinaltorphimine
    AUC
    area under the curve
    DA
    Dark Agouti
    %MPE
    percentage of maximum possible antinociceptive effect
    %MPE AUC
    area under the %MPE versus time curve
    %MPE.h
    units for %MPE AUC
    %CT
    degree of cross-tolerance (expressed as a percentage)
    i.t.
    intrathecal
    • Received March 29, 2000.
    • Accepted July 7, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 295 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 295, Issue 1
1 Oct 2000
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Research ArticleNEUROPHARMACOLOGY

Incomplete, Asymmetric, and Route-Dependent Cross-Tolerance between Oxycodone and Morphine in the Dark Agouti Rat

Carsten K. Nielsen, Fraser B. Ross and Maree T. Smith
Journal of Pharmacology and Experimental Therapeutics October 1, 2000, 295 (1) 91-99;

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Research ArticleNEUROPHARMACOLOGY

Incomplete, Asymmetric, and Route-Dependent Cross-Tolerance between Oxycodone and Morphine in the Dark Agouti Rat

Carsten K. Nielsen, Fraser B. Ross and Maree T. Smith
Journal of Pharmacology and Experimental Therapeutics October 1, 2000, 295 (1) 91-99;
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