Xylazine is an agonist at kappa opioid receptors and exhibits sex-specific responses to opioid antagonism.

Xylazine is in the unregulated drug supply at increasing rates, usually combined with fentanyl, necessitating understanding of its pharmacology. Despite commentary from politicians, and public health officials, it is unknown how xylazine impacts naloxone efficacy, and. few studies have examined it alone. Here, we examine the impact of xylazine alone and in combination with fentanyl on several behaviors in mice. Surprisingly, naloxone precipitates withdrawal from xylazine and fentanyl/xylazine coadministration, with enhanced sensitivity in females. Further, xylazine is a full agonist at kappa opioid receptors, a potential mechanism for its naloxone sensitivity. Finally, we demonstrate surprising effects of xylazine to kappa opioid antagonism, which are relevant for public health considerations. These data address an ongoing health crisis and will help inform critical policy and healthcare decisions.

Déclaration de conflit d'intérêts

Declaration of competing interest MLB, ACN, and ZAM are subcontracted by Epicypher® on an unrelated project. ND is an uncompensated board member of Remedy Alliance For The People, a 501(c)3 non-profit organization that distributes naloxone. BRL is on the SAB of several companies: Septerna, Onsero, Epiodyne, Escient; he has stock in Septerna; and he has had many technologies licensed by UNC to pharmaceutical and biotech companies. The remaining authors do not have any disclosures.