Xylazine is an Agonist at Kappa Opioid Receptors and Exhibits Sex-specific Responses to Opioid Antagonism

Overview

Journal Addict Neurosci

Date 2024 Aug 1

PMID 39086495

Authors

Madigan L Bedard

Xi-Ping Huang

Jackson G Murray

Alexandra C Nowlan

Sara Y Conley

Sarah E Mott

Samuel J Loyack

Calista A Cline

Caroline G Clodfelter

Nabarun Dasgupta

Brian Krumm

Bryan L Roth

Zoe A McElligott

Affiliations

Soon will be listed here.

Abstract

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.

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