Evidence that xylazine disrupts skin homeostasis by acting on epithelial cells through the kappa opioid receptor

The veterinary sedative and alpha-2 adrenergic receptor (α2AR) agonist xylazine, found in the illicit opioid supply, is associated with cutaneous wounds in humans. Here, we developed a larval zebrafish model of xylazine-induced tissue damage to investigate the mechanisms by which xylazine affects the skin. Xylazine treatment caused keratinocyte extrusion, tissue-wide skin contraction and disruption of basal keratinocyte cell-cell interactions in zebrafish larvae. Notably, other α2AR agonists did not recapitulate most of these effects. Xylazine was recently described as a kappa opioid receptor (κOR) agonist, and we found that both xylazine and a separate κOR agonist acted directly on epithelial cells to drive cellular contraction and disrupt tissue homeostasis. Our model suggests that xylazine disrupts skin homeostasis through a direct mechanism involving epithelial cells and κOR, which may be of importance for the treatment of these wounds.