Modeling features of addiction with an oral oxycodone self-administration paradigm

Abstract

Prescription opioid use is an initiating factor driving the current opioid epidemic. There are several challenges with modeling prescription opioid addiction. First, prescription opioids such as oxycodone are orally self-administered and have different pharmacokinetics and dynamics than morphine or fentanyl. This oral route of administration determines the pharmacokinetic profile, which is critical for establishing reliable drug-reinforcement associations in animals. Second, intravenous opioid self-administration is typically performed with intermittent drug self-administration sessions in a separate environment from the home cage. This does not recapitulate prescription opioid use, which is characterized by continuous drug access in the patients homes. To model features of prescription opioid use and the transition to abuse, we developed an oxycodone self-administration paradigm that is administered in the homecage. Mice voluntarily self-administer oxycodone in this paradigm without any taste modification such as sweeteners, and exhibit preference for oxycodone, escalation of intake, physical signs of dependence, reinstatement of seeking after withdrawal, and a subset of animals demonstrate drug taking that is resistant to negative consequences. This model is therefore translationally relevant and can be useful for studying the neurobiological substrates specifically relevant to prescription opioid abuse.

Estradiol Enhances the Development of Addiction-Like Features in a Female Rat Model of Opioid Use Disorder

“…However, recent studies have started to consider sex as a biological variable in OUD and, as with clinical findings, have reported notable sex differences in the development and expression of an addiction-like phenotype. For example, females self-administer higher levels of opioids, including heroin, fentanyl, and oxycodone, under extended-access conditions compared to males [19][20][21][22][23]. There are also sex differences in the pattern of opioid use under extended-access conditions with females showing greater escalation of heroin intake under the long-access procedure (i.e., fixed-ratio 1 access to the drug for 6 or more hours/day; [19,22]) and having greater fentanyl intake within active trials (or binge intake) under the intermittentaccess (IntA) procedure (fixed-ratio 1 access during 2, 5min trials/hr, 24 h/day; [23]) than males.…”

Machine learning and deep learning frameworks for the automated analysis of pain and opioid withdrawal behaviors

“…Notably, only one identified study focused on the automated analysis of opioid withdrawal behavior. In this preliminary study, Murphy and colleagues set out to establish a translational model of oral oxycodone self-administration using automated and open-source tools ( Murphy et al, 2021 ). Specifically, markerless pose estimation and subsequent supervised ML predictive classifiers for opioid withdrawal-related behavior were used in C57BL/6J mice that were trained to self-administer oxycodone orally for 12 days with ad libitum access.…”

“…Quantification and extraction of behavioral information were subsequently performed using SimBA, thus allowing Murphy and colleagues to assess jumping, climbing, rearing, grooming, tremors, and Euclidean distance of displacement of all body parts. Ultimately, this automated withdrawal behavioral analysis pipeline was able to detect and quantify physical signs of dependence that are consistent with opioid withdrawal syndrome in mice ( Murphy et al, 2021 ).…”

Comparing withdrawal- and anxiety-like behaviors following oral and subcutaneous oxycodone administration in C57BL/6 mice

“…In rodent studies, oxycodone use and dependence have been primarily modeled using operant intravenous self-administration procedures (Yuferov et al ., 2018; Zhang et al ., 2018; Blackwood et al ., 2020; Kimbrough et al ., 2020) and experimenter-delivered injections of oxycodone (Enga et al ., 2016; Wiebelhaus et al ., 2016; Nasseef et al ., 2019; Carper et al ., 2021). To more closely mimic oral misuse of prescription opioids in humans, researchers have recently investigated the behavioral and molecular mechanisms associated with volitional oral oxycodone consumption in rodents (Murphy et al ., 2021; Iyer et al ., 2022; Sharp et al ., 2021; Slivicki et al ., 2023). While both routes of administration have usefulness in modeling different aspects of OUD, a direct comparison of withdrawal- and anxiety-like behaviors following oral or parenteral administration of oxycodone has yet to be investigated.…”