Validation and characterization of oxycodone physical dependence in C57BL/6J mice

The Cannabinoid Receptor Type 1 Positive Allosteric Modulator ZCZ011 Attenuates Naloxone-Precipitated Diarrhea and Weight Loss in Oxycodone-Dependent Mice

“…CB 1 receptor orthosteric agonists and endocannabinoid catabolic enzyme inhibitors effectively attenuate opioid withdrawal; however, they also produce unwanted cannabimimetic effects, and antinociceptive tolerance and dependence upon repeated administration, which limits their potential clinical utility. Moreover, while clonidine has shown to reduce the frequency of withdrawal-induced jumps, paw flutters, and weight loss (Carper et al, 2021), its hypotensive effects limit its clinical use (Kuhlman et al, 1998;Stolbach and Hoffman, 2020). In contrast to combined FAAH/MAGL blockade, which substitutes for THC in the drug discrimination paradigm (Long, Nomura, et al, 2009), ZCZ011…”

“…Naloxone-Precipitated Oxycodone Withdrawal Model. To induce oxycodone dependence, counter-balanced groups of male and female mice were administered escalating doses of oxycodone over an eight day period as previously described (Enga et al, 2016;Carper et al, 2021). In brief, mice were administered s.c. injections of 9.0, 17.8, 23.7, then 33.0 mg/kg oxycodone (or saline) twice a day separated by approximately 7 h on days 1-2, 3-4, 5-6, and 7-8, respectively.…”

“…In brief, mice were administered s.c. injections of 9.0, 17.8, 23.7, then 33.0 mg/kg oxycodone (or saline) twice a day separated by approximately 7 h on days 1-2, 3-4, 5-6, and 7-8, respectively. On day nine, mice were administered 33 mg/kg oxycodone (or saline) followed by 1 mg/kg naloxone 2 h later to precipitate withdrawal (Enga et al, 2016;Carper et al, 2021) and withdrawal signs were assessed as previously described with some modifications (Ramesh et al, 2011).…”

“…1 and 2), preliminary experiments demonstrated that 75 mg/kg oxycodone and 40 mg/kg ZCZ011 did not exhibit behavioral effects (i.e., the expression of diarrhea, weight loss, jumps, paw flutters, or head shakes) in mice repeatedly administered saline and receiving a naloxone injection on day 9. In the dose-response experiment testing whether acute oxycodone administration will attenuate withdrawal responses, counter-balanced groups of male and female oxycodone-dependent ICR mice received an acute oxycodone injection (17, 33, or 75 mg/kg s.c.) or saline 30 min before naloxone administration with doses based on experiments conducted in C57BL/6J male mice (Carper et al, 2021).…”

“…Here we tested whether the CB 1 receptor PAM, ZCZ011, attenuates naloxone-precipitated withdrawal signs using an established mouse model of oxycodone-dependence (Enga et al, 2016;Carper et al, 2021). Oxycodone represents a widely used prescription opioid misused by 3.2 million people aged 12 or older in the United States (Substance Abuse and Mental Health Services Administration, 2020).…”