Oxycodone-like discriminative stimulus effects of fentanyl-related emerging drugs of abuse in mice

D Matthew Walentiny; Léa T Moisa; Patrick M Beardsley

doi:10.1016/j.neuropharm.2019.02.007

Oxycodone-like discriminative stimulus effects of fentanyl-related emerging drugs of abuse in mice

Neuropharmacology. 2019 May 15:150:210-216. doi: 10.1016/j.neuropharm.2019.02.007. Epub 2019 Feb 5.

Authors

D Matthew Walentiny¹, Léa T Moisa², Patrick M Beardsley³

Affiliations

¹ Department of Pharmacology & Toxicology, Virginia Commonwealth University, 1217 E. Marshall Street, Richmond, VA, 23298-0613, USA. Electronic address: david.walentiny@vcuhealth.org.
² Department of Pharmacology & Toxicology, Virginia Commonwealth University, 1217 E. Marshall Street, Richmond, VA, 23298-0613, USA.
³ Department of Pharmacology & Toxicology, Virginia Commonwealth University, 1217 E. Marshall Street, Richmond, VA, 23298-0613, USA; Institute for Drug and Alcohol Studies & Center for Biomarker Research and Personalized Medicine, Virginia Commonwealth University, 410 N. 12th Street, PO Box 980613, Richmond, VA, 23298-0613, USA.

PMID: 30735691
DOI: 10.1016/j.neuropharm.2019.02.007

Abstract

Background: Fentanyl and its structurally related compounds have emerged as the most significant contributors to opioid overdose fatalities in recent years. While there is abundant information about the pharmacological effects of fentanyl, far less is known of its more recently abused analogs. The objective of this study was to determine whether fentanyl and several fentanyl-related substances would engender oxycodone-like responding in a mouse model of oxycodone discrimination. Oxycodone was selected as the training drug due to its high selectivity for mu opioid receptors. Compounds that elicited oxycodone-like responding in this procedure would likely evoke overlapping subjective experiences.

Methods: Adult male C57BL/6 mice were trained to discriminate 1.3 mg/kg oxycodone from vehicle in a food-reinforced, two-lever choice procedure. Generalization tests were conducted with fentanyl and the following fentanyl-related compounds: ocfentanil, 3-furanyl fentanyl, crotonylfentanyl, and valerylfentanyl.

Results: Fentanyl and each of its analogs completely generalized to the 1.3 mg/kg oxycodone discriminative stimulus and naltrexone pretreatment significantly decreased oxycodone-like responding for each compound. Rank order potency for engendering oxycodone-appropriate responding was ocfentanil > fentanyl > 3-furanyl fentanyl ≈ crotonylfentanyl > oxycodone > valerylfentanyl. Drug doses that evoked full substitution also significantly suppressed response rates compared to vehicle.

Conclusions: These results indicate that the discriminative stimulus, and by extension, the interoceptive and subjective effects of the tested fentanyl analogs, overlap with those of oxycodone. These observations consequentially support the prediction that they would also engender the likelihood for abuse similar to oxycodone. This article is part of the Special Issue entitled 'Opioid Neuropharmacology: Advances in treating pain and opioid addiction'.

Keywords: Drug discrimination; Fentanyl; Fentanyl-related substance; New psychoactive substances; Opioid; Oxycodone.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Discrimination Learning / drug effects*
Fentanyl / analogs & derivatives
Fentanyl / pharmacology*
Furans / pharmacology
Generalization, Psychological / drug effects*
Male
Mice
Narcotics / pharmacology*
Oxycodone / pharmacology*
Piperidines / pharmacology

Substances

Furans
Narcotics
Piperidines
furanyl fentanyl
Oxycodone
ocfentanil
Fentanyl

Grants and funding

N01DA-17-8932/DA/NIDA NIH HHS/United States