Abstract
Prescription and illicit opioid use are a public health crisis, with the landscape shifting to fentanyl use. Since fentanyl is 100-fold more potent than morphine, its use is associated with a higher risk of fatal overdose that can be remediated through naloxone (Narcan) administration. However, recent reports indicate that xylazine, an anesthetic, is increasingly detected in accidental fentanyl overdose deaths. Anecdotal reports suggest that xylazine may prolong the fentanyl “high”, alter the onset of fentanyl withdrawal, and increase resistance to naloxone-induced reversal of overdose. To date no preclinical studies have evaluated the impacts of xylazine on fentanyl self-administration (SA; 2.5 μg/kg/infusion) or withdrawal to our knowledge. We established a rat model of xylazine/fentanyl co-SA and withdrawal and evaluated outcomes as a function of biological sex. When administered alone, chronic xylazine (2.5 mg/kg, IP) induced unique sex-specific withdrawal symptomatology whereby females showed delayed onset of signs and a possible enhancement of sensitivity to the motor-suppressing effects of xylazine. Xylazine reduced fentanyl consumption both male and female rats regardless of whether it was experimenter-administered or added to the intravenous fentanyl product (0.05. 0.10, and 0.5 mg/kg/infusion) when compared to fentanyl SA alone. Interestingly, this effect was dose-dependent when self-administered intravenously. Naloxone (0.1 mg/kg, SC) did not increase somatic signs of fentanyl withdrawal, regardless of the inclusion of xylazine in the fentanyl infusion in either sex; however, somatic signs of withdrawal were higher across timepoints in females after xylazine/fentanyl co-SA regardless of naloxone exposure as compared to females following fentanyl SA alone. Together, these results indicate that xylazine/fentanyl co-SA dose-dependently suppressed fentanyl intake in both sexes, and induced a unique withdrawal syndrome in females which was not altered by acute naloxone treatment.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Conflicts of interest: None
Funding Sources: This work was supported by the National Institutes of Health Grant DA055879, DA044479, DA046526, DA049130, and DA045881 (to CDG) and DA051377 and the Kentucky Medical Services Foundation Endowed Chair in Pharmacy (to TEP). All authors have no disclosures to declare.
Author Note: Transparency and openness guidelines: Materials are available upon request. We would like to thank Dr. Jeanie Kincer (Division of Laboratory Animal Resources, University of Kentucky) for initial assistance with determining intravenous xylazine dosing. We also thank Dr. Michael Bardo and Koby Shaykin for assistance with determining naloxone dosing and Dr. Justin Strickland for initial input on experimental design and data interpretation. We also thank Dr. Kevin Pearson for input on possible adipose mechanisms during withdrawal from xylazine and fentanyl co-SA.
