Work

Xylazine’s κ opioid agonist activity is not shared with other FDA-approved α 2 -adrenergic agonists

Year: 2026

Type: preprint

Abstract: Xylazine is a α 2 -adrenergic agonist typically used in as a sedative and analgesic in veterinary medicine. For some years, xylazine has been reported as an additive to fentanyl on the illicit drug market and has been associated with severe side-effects including severe ulcerations and potential amputations at the sites of injection along with an increased risk of respiratory depression and death. We recently reported that xylazine has modest κ opioid agonist activity in vitro and in vivo and asked if other α 2 -adrenergic agonists had similar off-target activities. To test this hypothesis, we profiled US FDA-approved α 2 -adrenergic agonists at 320 G protein coupled receptors (GPCRs) to identify potentially deleterious and/or beneficial off-targets. Although all other tested α 2 -adrenergic agonists were devoid of κ opioid agonist activity, each had a distinct pattern of activity at various GPCRs and differential patterns of signaling bias at α 2- receptor subtypes. These findings suggest potential molecular targets for both side-effects and therapeutic activities among known α 2 -adrenergic agonists.

Source: bioRxiv (Cold Spring Harbor Laboratory)

DOI: 10.64898/2026.03.04.709652

Authors: Xi-Ping Huang, Brian E Krumm, Madigan L Bedard, Zoe A McElligott, Bryan L Roth

Institutions: University of North Carolina at Chapel Hill, National Institute of Mental Health

Language: English

Topic: Receptor Mechanisms and Signaling

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: green

Funders: U.S. Department of Health and Human Services, National Institutes of Health, University of North Carolina at Chapel Hill, National Institute of Mental Health