Xylazine's κ relatively potent opioid agonist activity is not shared with other US Food and Drug Administration-approved α2-adrenergic agonists.

Xylazine is an α2-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 α2-adrenergic agonists had similar off-target activities. To test this hypothesis, we profiled US Food and Drug Administration-approved α2-adrenergic agonists at 320 G protein coupled receptors to identify potentially deleterious and/or beneficial off-targets. Although all other tested α2-adrenergic agonists were devoid of κ opioid agonist activity, each had a distinct pattern of activity at various G protein coupled receptors and differential patterns of signaling bias at α2-receptor subtypes. These findings suggest potential molecular targets for both side-effects and therapeutic activities among known α2-adrenergic agonists. SIGNIFICANCE STATEMENT: Xylazine was recently shown to be a κ-opioid receptor agonist and we examined other US Food and Drug Administration-approved α2-agonists for κ-opioid activity. Xylazine is unique in having κ-agonist activity.