Countering xylazine damage with natural products targeting cholinergic receptors
openNIDA - National Institute on Drug Abuse
SUMMARY
This R21 application is in response to the NIH Notice of Special Interest (NOSI, NOT-DA-24-012) to understand
xylazine misuse and consequences. Co-use of xylazine with opioids (frequently fentanyl) has become a major
threat to human health in the United States. No FDA-approved medications, including the opioid overdose
reversal medication naloxone, have efficacy in reversing xylazine’s effects. Although xylazine is a known non-
selective agonist of α2-adrenergic receptors (α2-ARs), none of the α2-AR antagonists can effectively reverse all
deleterious effects induced by xylazine, from central nervous system depression to severe skin lesions and
infection, suggesting that most harmful manifestations of xylazine probably result from xylazine’s action on
receptors other than α2-AR. The goal of this application is to fill a critical knowledge gap in understanding the
pharmacological and pathological impact of xylazine and identify effective compounds that are proven "safe for
human use" and can offset xylazine-caused damage. On which major receptors other than α2-AR does xylazine
act? What are the functional consequences and immune responses due to xylazine’s actions? What compounds
can effectively reverse damage induced by xylazine? We strive to answer these questions. Our preliminary
studies show that xylazine inhibits α7 nicotinic acetylcholine receptors (α7nAChRs) and the inhibition can be
offset by a class of natural products. Inhibiting Ca2+-conducting α7nAChRs is known to produce a broad spectrum
of negative impacts because of the widespread expression of α7nAChRs across various cells in the human body.
α7nAChRs play an important role in regulating the central and peripheral nervous systems as well as the
cholinergic anti-inflammatory pathway. Here, we will investigate xylazine-induced functional changes of
α7nAChR in different types of human cells and identify natural products that can effectively reverse the xylazine-
induced functional consequences. We will also investigate xylazine-triggered cell death and inflammatory
responses and determine how effectively the identified natural products reverse xylazine-caused damage. The
influence of fentanyl on xylazine’s effects will be investigated to provide much needed insight into complications
from xylazine-opioid misuse. Cell types to be investigated include human neural and skin cells that natively
express α7nAChRs and opioid receptors and are clinically relevant to the organs and tissues linked to the
deleterious effects of xylazine. The outcomes from the proposed studies will broaden the current understanding
of xylazine misuse and lead to potential treatment strategies for rapid therapeutic deployment to xylazine/opioid
users.
Up to $434K
health research