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

Abstract

Incidence of prescription opioid abuse and overdose, often led by oxycodone, continues to increase, producing twice as many overdose deaths as heroin. Surprisingly, preclinical reports relevant to oxycodone's abuse-related effects are relatively sparse considering its history and patient usage. The goal of this study was to characterize dose-and time-dependent effects of acute and repeated oxycodone administration in a frequencyrate intracranial self-stimulation (ICSS) procedure, an assay often predictive of drug-related reinforcing effects, in male Sprague-Dawley rats. We hypothesized that oxycodone would produce a biphasic profile of rate-increasing and ratedecreasing effects maintained by ICSS similar to m-opioid receptor agonists. Oxycodone (0.03, 0.3, 1, and 3 mg/kg, s.c.) produced dose-and time-dependent alterations on ICSS, with the predicted biphasic profile of rate-increasing effects at lower stimulation frequencies followed by rate-decreasing effects at higher frequencies. Peak effects were observed between 30 and 60 minutes, which were reversed by naloxone pretreatment (30 minutes). Tolerance to rate-decreasing effects was observed over a 5-day period when rats were treated with 1 mg/kg oxycodone twice a day. Subsequently, the dosing regimen was increased to 3 mg/kg twice a day over 10 days, although further marked tolerance did not develop. When then challenged with 10 mg/kg naloxone, a significant suppression below baseline levels of ICSS-maintained responding occurred indicative of dependence that recovered to baseline within 5 hours. The results of this study provide the first report of acute and chronic effects of oxycodone on responding maintained by ICSS presentation and the use of ICSS-maintained responding to characterize its tolerance and dependence effects.

Oxycodone physical dependence and its oral self-administration in C57BL/6J mice

“…subcutaneous administration as inferred by naloxone-precipitated somatic signs of opiate-like withdrawal syndrome. We previously reported that morphine-dependent rhesus monkeys demonstrate cross-dependency to oxycodone (Beardsley et al, 2004), and that naloxone can precipitate disruptions of lever pressing maintained by intra-cranial self-stimulation in rats chronically-treated with oxycodone suggestive of dependence (Wiebelhaus et al, 2016). Thus, oxycodone demonstrates opiate-like dependence effects across species including mice, rats and rhesus monkeys.…”

“…Disruption of operant behavior can also be used to infer a type of “behavioral dependence” even when not accompanied by somatic signs of withdrawal (Schuster and Thompson, 1969). Naloxone-precipitated withdrawal disruption of lever pressing maintained by intracranial self-stimulation in rats indicative of behavioral dependence has also been reported (Wiebelhaus et al, 2016). …”

BOLD Imaging in Awake Wild-Type and Mu-Opioid Receptor Knock-Out Mice Reveals On-Target Activation Maps in Response to Oxycodone

“…OXY abuse is well documented, much of which can be attributed to drug dependence and withdrawal as reported in clinical (Jones et al, 2011; Mars et al, 2014) and preclinical studies (Hutchinson et al, 2009; Wiebelhaus et al, 2016). In addition, OXY has reinforcing effects as measured by self-administration and condition place preference studies in rodents (Beardsley et al, 2004; Zhang Y. et al, 2009; Rutten et al, 2011; Bryant et al, 2014; Zhang et al, 2015).…”

Regular physical activity prevents development of chronic muscle pain through modulation of supraspinal opioid and serotonergic mechanisms

“…were dissolved in 0.9% sterile saline for systemic delivery, and dosing was based on previously published data in mice. 67 , 68 , 70 , 109 For microinjection, naloxone hydrochloride was dissolved in saline at a concentration of 10 nmol/0.2 μL; dosing was based on previously published data in mice. 12 , 14 Fluoxetine doses (Sigma-Aldrich) were extrapolated from previous reports and tested in preliminary studies.…”