Effects of the veterinary anesthetic xylazine on the discriminative stimulus and rate-decreasing effects of fentanyl in rats.

Abstract

Adulterants such as the α2-adrenoreceptor agonist xylazine in the illicit drug supply can complicate overdose and treatment plans for patients. Xylazine and other α2-adrenoreceptor agonists are reported to extend the duration of the µ opioid receptor agonist fentanyl which is short acting relative to other opioids (Friedman et al., 2022; Meert and De Kock, 1994). To test the effects of xylazine on the subjective effects of fentanyl, 12 Sprague-Dawley rats were trained to discriminate between saline or 0.01mg/kg fentanyl in a two-lever drug discrimination procedure. Doses of fentanyl (0.001-0.032mg/kg) produced increasing fentanyl lever responding and reduced response rates. A dose of 1.0mg/kg xylazine produced approximately 40% fentanyl lever responding and markedly reduced response rates. Co-administration of xylazine produced small, rightward shifts in the dose-response curves for the stimulus effects of fentanyl. The effects of fentanyl were blocked by the opioid antagonist naloxone, but not by the α2-adrenoreceptor antagonist idazoxan. The partial substitution of xylazine for fentanyl and the rate-decreasing effects of xylazine were blocked by idazoxan but not naloxone. The discriminative stimulus effects of 0.01mg/kg fentanyl decreased to 20% after 30min yet the partial substitution of 1.0mg/kg xylazine for fentanyl remained at 40% for 30min. Co-administration of xylazine augmented fentanyl-lever responding after 30min which was blocked by naloxone. These data demonstrate that although xylazine partially substitutes for the discriminative stimulus effects of fentanyl through α2-adrenoreceptors, xylazine can prolong the time course of fentanyl in a naloxone reversible manner.