Oxycodone is a selective μ-opioid receptor agonist in rodent behavioural tests

Bailey CP1, Dolan S2, Corbett AD2, McKnight AT, Beckett SR3, Marsden CA3, Henderson G1. 1Department of Pharmacology, University of Bristol, Bristol, BS8 1TD. 2School of Life Sciences, Glasgow Caledonian University, Glasgow, G4 0BA. 3School of Biomedical Sciences, University of Nottingham, Nottingham NG7 2UH.

Oxycodone has been in clinical use for over 80 years, yet there has been little research into its pharmacology. In particular, it is unclear whether its therapeutic actions are mediated by μ- or κ-opioid receptors (Ross & Smith, 1997). To investigate this, we examined oxycodone-induced analgesia, conditioned place-preference (CPP) and respiratory depression, using the following experimental tools: morphine ( μ-opioid-receptor agonist), U-69593 ( κ-opioid receptor agonist), naloxone (non-specific opioid- antagonist) and nor-BNI (long lasting κ-opioid-antagonist, and short acting μ-opioid antagonist). Analgesia and respiratory depression data were analysed by Student’s t-test, CPP data were analysed by ANOVA and Tukey’s post-hoc test.

Hindpaw withdrawal latency (s) to thermal stimulation (female Wistar rats, 200-250g; n=6/group) was measured every 15 min for 120 min following s.c. drug administration. Data are expressed as area under curve (AUC). Oxycodone-induced analgesia was blocked by pre-(15 min) treatment with naloxone (1 mg kg-1) (AUC: 2372±173 vs.1087 ± 93 s min-1, P < 0.05) but not pre- (24 h) treatment with nor-BNI (5 mg kg-1 ) (Table 1; * p< 0.05 vs. U69593).

Table 1. Effects of nor-BNI on opioid agonist-induced analgesia

Conditioned place-preference (male hooded Lister rats, 8-12 weeks old; n=7-8/group) was performed with an initial pre-conditioning day and 2 consecutive days of conditioning; testing was on the 4 th day (adapted from Harper et al., 2006). Data are expressed as % time spent in conditioned side following conditioning/time spent during pre-conditioning.Following conditioning with oxycodone (3 mg kg -1, i.p.), rats spent more time in the conditioned area (127.3±12.4 %), an effect inhibited by naloxone (1 mg kg -1, i.p; 90.4±8.6 %; P <0.05) but not by nor-BNI (117.9±9.4 %).
Respiratory depression (male CD1 mice, 6 weeks old; n=3-5/group) was measured by whole-animal plethysmography. Breath frequency was significantly reduced 30min after i.p. injection of morphine (10 mg kg -1; 517±16 vs. 279±31 breaths/min; P < 0.05) and oxycodone (2 mg kg -1; 549±22 vs. 237±6 breaths/min; P<0.05), but not by U69593 (3 mg kg -1; 481±37 vs. 431±31 breaths/min). Pre-(24 h) treatment with nor-BNI (10mg kg -1) reduced the extent of, but did not block, oxycodone-induced respiratory depression (519±19 vs. 327±21 breaths/min; P < 0.05) , however, this is likely due to residual μ-opioid blockade by nor-BNI rather than by κ-opioid antagonism.

These data suggest that oxycodone causes analgesia, reward and respiratory depression by activating the m -opioid receptor, and that oxycodone is not a κ-opioid agonist.

Harper LK et al. (2006) Pharmacol Biochem Behav 83:114-121
Ross FB & Smith MT (1997) Pain 73:151-157