Evaluating the reinforcing properties of oxycodone and oxymorphone using intravenous drug self-administration in male rats

Abstract

Oxycodone, a commonly abused opioid, and its metabolite oxymorphone are agonists at the μ-opioid receptor. While oxymorphone is more potent, and clinical data suggests a greater abuse liability, there is little data comparing them in preclinical models. We examined their reinforcing properties using the intravenous (IV) self-administration method. Male Wistar Han rats were implanted with IV catheters and trained to lever press for infusions of oxycodone and oxymorphone. Dose response curves were assessed using fixed ratio (FR) 1, FR3, FR5 and progressive ratio (PR) schedules. Responding was then extinguished and drug priming-induced reinstatement, a model of relapse, was assessed. Microdialysis was used to assess central concentrations of oxymorphone following IV oxycodone. Under FR1 schedules, in both oxycodone and oxymorphone self-administering rats, active lever pressing and infusions earned decreased with increasing dose, while intake increased, however the shape of the dose response curves differed. Oxymorphone, compared to oxycodone, exhibited a leftward shift in the dose-response curve, indicative of higher potency, but also a shallower slope and lower maximal active lever pressing and infusions. On the PR schedule, the highest breakpoint was observed for oxymorphone. Oxycodone (0.25 mg/kg) induced significant drug-priming reinstatement after extinction, while an equipotent dose of oxymorphone (0.025 mg/kg) approached significant reinstatement. After a bolus IV injection of oxycodone, oxymorphone was present in the cerebrospinal fluid at approximately 1/250th the concentration of oxycodone. These findings highlight distinct self-administration patterns between oxycodone, which is metabolized to oxymorphone in vivo, and oxymorphone itself, suggesting differences beyond potency at the μ-opioid receptor.