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 <i>Xenopus</i> 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.