Incomplete, Asymmetric, and Route-Dependent Cross- Tolerance between Oxycodone and Morphine in the Dark Agouti Rat 1

ABSTRACT Our previous studies indicate that oxycodone is a putative -opioid agonist, whereas morphine is a well documented -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 crosstolerance (Ϸ24%) 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 (Ϸ71% and Ϸ54%, respectively) in rats rendered tolerant to oxycodone. Taken together, these findings suggest that, after parenteral but not supraspinal administration, oxycodone is metabolized to a -opioid agonist metabolite, thereby explaining asymmetric and incomplete cross-tolerance between oxycodone and morphine. Morphine is recommended by the World Health Organization as the drug of choice for the management of moderate to severe cancer pain (WHO, 1986). Tolerance to the pain-relieving effects of opioids is a problem that may be encountered in a clinical setting in patients receiving these drugs for the relief of chronic pain. Antinociceptive tolerance is well documented in experimental animals such as rats and mice and is characterized by a marked reduction in the painrelieving effects of an opioid such as morphine after chronic administration. This phenomenon has been shown by numerous laboratories for a range of antinociceptive tests Oxycodone has been used clinically for over 80 years, but its pharmacology has been studied only relatively recently. The analgesic actions of oxycodone are comparable to those of morphine and are mediated primarily in the central nervous system. Oxycodone has been reported to be ϳ1.5 times more potent than morphine when administered by both the i.v. and oral routes for postoperative and cancer pain relief with fewer side-effects than morphine The intrinsic antinociceptive effects of oxycodone are mediated by central nervous system opioid receptors, because they are completely attenuated by i.c.v. naloxone, a universal opioid receptor antagonis