Discriminative Stimulus Effects of Mu Opioid Receptor Agonists in Rats Discriminating Fentanyl: Differential Antagonism by Naltrexone

Abstract

The opioid crisis continues despite the availability of medications that are effective in some patients. A significant number of deaths caused by opioids involve fentanyl and/or one of its very potent analogues (e.g., carfentanil). Many fentanyl analogs have not been studied extensively in vivo. The current study compared the discriminative stimulus effects of fentanyl and carfentanil and their antagonism by naltrexone. Seven male Sprague‐Dawley rats were trained to discriminate a 0.01 mg/kg fentanyl from saline while responding under a fixed‐ratio 10 schedule of food presentation. Dose effect curves were determined for the opioid receptor agonists alone: fentanyl (0.001–0.1 mg/kg) and carfentanil (0.0001–0.0032 mg/kg). Dose effect curves for fentanyl and carfentanil were then redetermined following a 15‐minute pretreatment with 0.1 mg/kg naltrexone. All drugs were delivered intraperitoneally. Fentanyl and carfentanil dosedependently increased responding on the fentanyl‐associated lever and at larger doses decreased the rate of lever pressing. Carfentanil was approximately 10‐fold more potent than fentanyl at eliciting >90% responding on the fentanyl‐associated lever. Pretreatment with 0.1 mg/kg naltrexone shifted the fentanyl dose‐effect curve 10‐fold rightward whereas the same dose of naltrexone shifted the carfentanil curve only 3‐fold rightward. Differences in the effectiveness of naltrexone to attenuate the discriminative stimulus effects of fentanyl and carfentanil suggests that there may be differences in how fentanyl and carfentanil exert their discriminative stimulus effects. Further evaluation of potential pharmacological and behavioral differences between fentanyl and carfentanil is needed and might provide important insights regarding the apparently increased toxicity of carfentanil, compared with other opioids, in humans.Support or Funding InformationAQ‐0039 from the Welch Foundation