Discriminative Stimulus, Reinforcing, Physical Dependence, and Antinociceptive Effects of Oxycodone in Mice, Rats, and Rhesus Monkeys.

Abstract

Despite oxycodone's (4,5-epoxy-14-hydroxy-3-methoxy-17-methylmorphinan-6-one) history of clinical use and the attention it has received as a drug of abuse, few reports have documented its pharmacology's relevance to its abuse or its mechanism of action. The purposes of the present study were to further characterize the analgesic effects of oxycodone, its mechanism of action, and its effects in terms of its relevance to its abuse liability. The results indicate that oxycodone had potent antinociceptive effects in the mouse paraphenylquinone writhing, hot-plate, and tail-flick assays, in which it appeared to be acting as a mu-opioid receptor agonist. It generalized to the heroin discriminative stimulus and served as a positive reinforcer in rats and completely suppressed withdrawal signs in morphine-dependent rhesus monkeys. These results suggest that the analgesic and abuse liability effects of oxycodone are likely mediated through mu-opioid receptors and provide the first laboratory report of its discriminative stimulus, reinforcing, and morphine cross-dependency effects.

Effects of Acute and Repeated Administration of Oxycodone and Naloxone-Precipitated Withdrawal on Intracranial Self-Stimulation in Rats

“…In particular, there have been relatively few preclinical reports characterizing the reinforcing and dependence-producing properties of the drug. In terms of its reinforcing-related effects, oxycodone has been reported to be self-administered by laboratory animals, including rats (Beardsley et al, 2004) and mice (Zhang et al, 2009(Zhang et al, , 2015. Oxycodone also produces conditioned place preference in rats (Rutten et al, 2011) and mice Kirkpatrick and Bryant, 2014).…”

“…The authors reported that they did not analyze the somatic signs of oxycodone withdrawal because of the "severity of … withdrawal" it produced (Hutchinson et al, 2009). Beardsley et al (2004) reported that oxycodone dose-dependently suppressed signs of spontaneous withdrawal in morphine-dependent monkeys and concluded that oxycodone shared cross-dependence with morphine. Also pertinent to the abuse-related effects of oxycodone is its ability to induce locomotor sensitization and its discriminative stimulus effects.…”

“…Also pertinent to the abuse-related effects of oxycodone is its ability to induce locomotor sensitization and its discriminative stimulus effects. Oxycodone can induce locomotor sensitization (Liu et al, 2005;Niikura et al, 2013;Bryant et al, 2014) and has heroin-like discriminative stimulus effects with a similar potency to heroin (Beardsley et al, 2004).…”

Abuse Liability of Prescription Opioids Compared to Heroin in Morphine-Maintained Heroin Abusers

“…Surprisingly, few studies in laboratory animals (Beardsley et al, 2004;Woods et al, 2002) and no studies in humans have been conducted to examine systematically the reinforcing effects of some of the most commonly abused prescription opioids, such as oxycodone. Fentanyl abuse has also increased substantially in the last decade, and although the reinforcing effects of fentanyl have been examined in some detail in laboratory animals (eg Ko et al, 2002;Morgan et al, 2002), few studies have examined its reinforcing effects in humans (Zacny et al, 1996b) and no studies have characterized its reinforcing effects in opioid abusers.…”

Regulation of Gene Expression in Brain Tissues of Rats Repeatedly Treated by the Highly Abused Opioid Agonist, Oxycodone: Microarray Profiling and Gene Mapping Analysis

“…Oxycodone has been thought to exert its pharmacological activity through activation of -opioid receptors (Nielsen et al, 2000); however, other studies suggested that the analgesic and abuse effects of oxycodone are probably mediated through -opioid receptors (Beardsley et al, 2004;Nozaki and Kamei, 2007). Oxycodone is the most often prescribed opioid agonist in the United States (Hays, 2004).…”