Effects of orally self-administered furanyl fentanyl and acryl fentanyl in mice: antinociception, dependence and withdrawal, and defense of consumption.

Oral use of illicit fentanyl formulations is common, and these preparations may be contaminated with fentanyl analogs (FAs) with unknown pharmacological and toxicological properties. Route of administration impacts pharmacological effects, and pharmacokinetic or pharmacodynamic properties of oral fentanyl and FAs could influence aspects of opioid use disorder that are not necessarily present in animal models involving other routes of administration. We established oral consumption of water, or solutions of the FAs furanyl fentanyl and acryl fentanyl in C57 B l/6N mice. Consumption of pharmacologically-relevant concentrations of the FAs was reliably engendered, verified by induction of opioid-mediated antinociceptive effects in a warm-water tail withdrawal procedure, hypothermic effects, and observation of antagonist-precipitated withdrawal. When maintenance solutions were adulterated with the bitter tastant quinine, water control mice decreased their consumption, but mice consuming FA solutions defended their consumption, even at quinine concentrations that suppressed water drinking. Brief access to supplemental water, injection of the μ-opioid antagonist naltrexone, or administration of the μ-opioid agonist morphine all attenuated the defense of FA consumption. In all cases, the abuse-related effects of acryl fentanyl were greater than those of furanyl fentanyl. Consumption of acryl fentanyl also abolished weight gain across the study, and disrupted nest-building. The results of these experiments suggest that mice drinking furanyl fentanyl or acryl fentanyl experience opioid-mediated effects including antinociception, dependence and withdrawal, and abuse-related subjective effects, and provide proof of concept for use of this model to assess pharmacological and non-pharmacological manipulations which may attenuate the reinforcing effects of oral fentanyl and FAs.