Competitive Antagonism of Xylazine on α7 Nicotinic Acetylcholine Receptors and Reversal by Curcuminoids

Co-use of xylazine with opioids is a major health threat in the United States. However, a critical knowledge gap exists in the understanding of xylazine-induced pharmacological and pathological impact. Xylazine is mostly known as an agonist of α2-adrenergic receptors (α2-ARs), but its deleterious effects on humans cannot be fully reversed by the α2-AR antagonists, suggesting the possibility that xylazine targets receptors other than α2-ARs. Here, we report the discovery of α7 nicotinic acetylcholine receptors (α7 nAChRs) as targets of xylazine. In Xenopus oocytes expressing α7 nAChRs, xylazine competitively antagonizes channel currents elicited by the agonist acetylcholine. In PC12 cells, xylazine suppresses choline-stimulated intracellular calcium ([Ca²⁺]_in) transients that are mediated by endogenously expressed α7 nAChRs. Furthermore, we find that curcuminoids, ivermectin, and the α7-specific positive allosteric modulator PNU120596 can effectively offset the xylazine inhibition of α7 nAChRs. Considering the prominent role of α7 nAChRs in the cholinergic anti-inflammatory pathway and wide expression in the human body, our findings present a potential new strategy to reverse xylazine-caused damage using curcuminoids or repurposing ivermectin. This α7 nAChR-focused strategy may offer an immediate deployment that is likely effective in improving xylazine-related treatment outcomes.