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, intraperitoneal) 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 in 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, subcutaneous injection) 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 time points 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 that was not altered by acute naloxone treatment.

Document Type

Article

Publication Date

2023

Notes/Citation Information

© 2023 American Psychological Association

Digital Object Identifier (DOI)

https://doi.org/10.1037/pha0000670

Funding Information

This work was supported by the National Institutes of Health Grants DA055879, DA044479, DA046526, DA049130, and DA045881 (to Cassandra D. Gipson) and DA051377 and the Kentucky Medical Services Foundation Endowed Chair in Pharmacy (to Thomas E. Prisinzano). Cassandra D. Gipson and Terry D. Hinds, Jr. received funding from Grant DA058933 from the National Institutes of Health.

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