Xylazine is an agonist at kappa opioid receptors and exhibits sex-specific responses to naloxone administration

Xylazine has been found in the unregulated drug supply at increasing rates, usually in combination with fentanyl. It has become critical to understand its basic pharmacology, how it impacts behavior, and how it interacts with fentanyl in rodent models of opioid administration. Despite commentary from scientists, politicians, and public health officials, it is not known if xylazine impacts the efficacy of naloxone, the opioid receptor antagonist used to reverse opioid induced respiratory depression. Furthermore, few studies have examined the effects of xylazine alone, without co-administration of ketamine. Here, we examine the impact of xylazine alone and in combination with fentanyl on several key behaviors in male and female mice. We demonstrate differential locomotor responses by dose and sex to xylazine. Surprisingly, our results further indicate that naloxone precipitates withdrawal from xylazine and a fentanyl/xylazine combination, in both sexes, with enhanced sensitivity in females. Further, we show that xylazine is a full agonist at the kappa opioid receptor, a potential mechanism for its naloxone sensitivity. One-Sentence SummaryWe present surprising new insights into xylazine and fentanyl pharmacology with immediate implications for clinical practice and frontline public health.