Incomplete, asymmetric, and route-dependent cross-tolerance between oxycodone and morphine in the Dark Agouti rat

Nielsen, C. K., Ross, F. B. and Smith, M. T. (2000) Incomplete, asymmetric, and route-dependent cross-tolerance between oxycodone and morphine in the Dark Agouti rat. Journal of Pharmacology and Experimental Therapeutics, 295 1: 91-99.


Author Nielsen, C. K.
Ross, F. B.
Smith, M. T.
Title Incomplete, asymmetric, and route-dependent cross-tolerance between oxycodone and morphine in the Dark Agouti rat
Journal name Journal of Pharmacology and Experimental Therapeutics   Check publisher's open access policy
ISSN 1521-0103
Publication date 2000-01-01
Year available 2000
Sub-type Article (original research)
Open Access Status Not yet assessed
Volume 295
Issue 1
Start page 91
End page 99
Total pages 9
Editor S.J. Enna
Place of publication USA
Publisher American Society for Pharmacology & Experimental Therapeutics
Language eng
Subject C1
320502 Basic Pharmacology
670403 Treatments (e.g. chemicals, antibiotics)
Abstract Our previous studies indicate that oxycodone is a putative kappa-opioid agonist, whereas morphine is a well documented mu-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 (approximate to 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 (approximate to 71% and approximate to 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 mu-opioid agonist metabolite, thereby explaining asymmetric and incomplete cross-tolerance between oxycodone and morphine.
Keyword Pharmacology & Pharmacy
Controlled-release Oxycodone
Food Presentation
Opioid Agonists
Analgesia
Morphine-3-glucuronide
Metabolites
Schedule
Pain
Pharmacokinetics
Codeine
Q-Index Code C1
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Centre for Integrated Preclinical Drug Development Publications
 
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Created: Mon, 13 Aug 2007, 21:57:15 EST