TY - JOUR
T1 - Characterization of the Discriminative Stimulus Effects of Binary Mixtures of Mu Opioid Receptor Agonists in Rats Discriminating Fentanyl
AU - Flynn, Shawn M.
AU - France, Charles P.
N1 - Publisher Copyright:
Copyright © 2022 by The American Society for Pharmacology and Experimental Therapeutics.
PY - 2022/3/1
Y1 - 2022/3/1
N2 - Drug overdose deaths involving synthetic opioids, primarily fentanyl, have risen dramatically over the past decade and are currently the driving force of the opioid epidemic in the United States. Fentanyl analogs with greater potency than fentanyl (e.g., carfentanil) pose serious risk to public health. Although fentanyl analogs are primarily encountered by humans as constituents of a mixture of drugs, research has primarily evaluated the effects of these drugs alone. The present study characterized interactions between mu opioid receptor agonists in seven male Sprague-Dawley rats trained to discriminate 10 lg/kg fentanyl from saline while responding under a fixed-ratio 10 schedule of food presentation. Dose-effect curves were determined for each drug alone and in binary mixtures (fentanyl:heroin, fentanyl:carfentanil, and heroin:carfentanil) at fixed-dose ratios of 3:1, 1:1, and 1:3 relative to the ED50 for each drug when given alone. Dose addition analyses were used to determine the nature of the drug-drug interaction for each mixture. Additive interactions were observed for all binary mixtures at each fixed dose ratio, except the 1:3 fentanyl:carfentanil mixture, which exhibited supra-additive effects at the 80% effect level. These results suggest a lack of a significant interaction between the discriminative stimulus effects of these mu opioid receptor agonists at the doses tested in this study. Future studies expanding these findings to the respiratory depressant effects of these drugs are of significant importance to rule out possible interactions directly relevant to opioid overdose that occur at doses much larger than those tested in this study.
AB - Drug overdose deaths involving synthetic opioids, primarily fentanyl, have risen dramatically over the past decade and are currently the driving force of the opioid epidemic in the United States. Fentanyl analogs with greater potency than fentanyl (e.g., carfentanil) pose serious risk to public health. Although fentanyl analogs are primarily encountered by humans as constituents of a mixture of drugs, research has primarily evaluated the effects of these drugs alone. The present study characterized interactions between mu opioid receptor agonists in seven male Sprague-Dawley rats trained to discriminate 10 lg/kg fentanyl from saline while responding under a fixed-ratio 10 schedule of food presentation. Dose-effect curves were determined for each drug alone and in binary mixtures (fentanyl:heroin, fentanyl:carfentanil, and heroin:carfentanil) at fixed-dose ratios of 3:1, 1:1, and 1:3 relative to the ED50 for each drug when given alone. Dose addition analyses were used to determine the nature of the drug-drug interaction for each mixture. Additive interactions were observed for all binary mixtures at each fixed dose ratio, except the 1:3 fentanyl:carfentanil mixture, which exhibited supra-additive effects at the 80% effect level. These results suggest a lack of a significant interaction between the discriminative stimulus effects of these mu opioid receptor agonists at the doses tested in this study. Future studies expanding these findings to the respiratory depressant effects of these drugs are of significant importance to rule out possible interactions directly relevant to opioid overdose that occur at doses much larger than those tested in this study.
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U2 - 10.1124/jpet.121.000912
DO - 10.1124/jpet.121.000912
M3 - Article
C2 - 34903563
AN - SCOPUS:85125681936
SN - 0022-3565
VL - 380
SP - 171
EP - 179
JO - Journal of Pharmacology and Experimental Therapeutics
JF - Journal of Pharmacology and Experimental Therapeutics
IS - 3
ER -