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

Our previous studies indicate that oxycodone is a putative kappa-opioid ago nist, whereas morphine is a well documented mu-opioid agonist. Because ther e is limited information regarding the development of tolerance to oxycodon e, this study was designed to 1) document the development of tolerance to t he antinociceptive effects of chronically infused i.v. oxycodone relative t o that for i.v. morphine and 2) quantify the degree of antinociceptive cros s-tolerance between morphine and oxycodone in adult male Dark Agouti (DA) r ats. Antinociceptive testing was performed using the tail-flick latency tes t. Complete antinociceptive tolerance was achieved in 48 to 84 h after chro nic infusion of equi-antinociceptive doses of i.v. oxycodone (2.5 mg/24 h a nd 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 oxycod one 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 degre e 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. T aken together, these findings suggest that, after parenteral but not supras pinal administration, oxycodone is metabolized to a mu-opioid agonist metab olite, thereby explaining asymmetric and incomplete cross-tolerance between oxycodone and morphine.