Discriminative stimulus effects of carfentanil in rats discriminating fentanyl: Differential antagonism by naltrexone

Drug Alcohol Depend. 2021 Apr 1;221:108599. doi: 10.1016/j.drugalcdep.2021.108599. Epub 2021 Feb 13.


Background: A significant number of deaths caused by opioids involve fentanyl and/or one of its very potent analogs (e.g., carfentanil). Some clinical reports suggest larger doses of opioid receptor antagonists may be required to reverse the effects of carfentanil compared with other opioid receptor agonists, although this has not been examined extensively in vivo. The current study compared the discriminative stimulus effects of fentanyl, carfentanil, and heroin, and their antagonism by naltrexone.

Methods: Eight male Sprague-Dawley rats were trained to discriminate 10.0 μg/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 fentanyl (1.0-32.0 μg/kg), carfentanil (0.1-3.2 μg/kg), and heroin (10.0-320.0 μg/kg), then redetermined following a 15-minute pretreatment with 0.1 mg/kg naltrexone.

Results: Fentanyl, carfentanil, and heroin dose-dependently increased responding on the fentanyl-associated lever and decreased the rate of lever pressing. Carfentanil and heroin were approximately 10-fold more and less potent, respectively, than fentanyl at eliciting >80 % responding on the fentanyl-associated lever. Pretreatment with 0.1 mg/kg naltrexone resulted in a significant rightward shift in the fentanyl and heroin but not carfentanil dose-effect curves.

Conclusions: Differences in the effectiveness of naltrexone to attenuate the discriminative stimulus effects of carfentanil, compared with fentanyl and heroin, suggest that there may be differences in how carfentanil exerts its discriminative stimulus effects compared with other opioids. Further evaluation is needed of potential pharmacological and behavioral differences between carfentanil and other opioids, particularly in the context of toxicity.

Keywords: Carfentanil; Drug discrimination; Fentanyl; Heroin; Naltrexone; Opioid.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesics, Opioid / pharmacology
  • Animals
  • Dose-Response Relationship, Drug
  • Fentanyl / analogs & derivatives*
  • Fentanyl / pharmacology
  • Heroin / pharmacology
  • Male
  • Naltrexone / pharmacology*
  • Narcotic Antagonists / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Opioid, mu


  • Analgesics, Opioid
  • Narcotic Antagonists
  • Receptors, Opioid, mu
  • Naltrexone
  • Heroin
  • carfentanil
  • Fentanyl