Combined treatment with naloxone and the alpha2 adrenoceptor antagonist atipamezole reversed brain hypoxia induced by a fentanyl-xylazine mixture in a rat model

Study Authors Shin Choi, Mike Noya, Matthew Irwin
and Eugene Kiyatkin

Featured Paper of the Month – May 2024

Summary

Xylazine, an increasingly abused drug mixed with fentanyl, leads to devastating respiratory issues during fentanyl-xylazine overdose. Despite naloxone being the primary treatment, it falls short in fully reversing the hypoxic effects of the drug mixture. Our study suggests that supplementing naloxone with atipamezole, a xylazine antagonist, provides a more effective and thorough solution for addressing brain hypoxia caused by fentanyl-xylazine mixture.

Publication Information

Choi, Shinbe; Irwin, Matthew R; Noya, Michael R; Shaham, Yavin; Kiyatkin, Eugene A

Combined treatment with naloxone and the alpha2 adrenoceptor antagonist atipamezole reversed brain hypoxia induced by a fentanyl-xylazine mixture in a rat model Journal Article

In: Neuropsychopharmacology, 2023, ISSN: 1740-634X.

Abstract | Links

@article{pmid38123817,

title = {Combined treatment with naloxone and the alpha2 adrenoceptor antagonist atipamezole reversed brain hypoxia induced by a fentanyl-xylazine mixture in a rat model},

author = {Shinbe Choi and Matthew R Irwin and Michael R Noya and Yavin Shaham and Eugene A Kiyatkin},

url = {https://pubmed.ncbi.nlm.nih.gov/38123817/},

doi = {10.1038/s41386-023-01782-2},

issn = {1740-634X},

year  = {2023},

date = {2023-12-01},

urldate = {2023-12-01},

journal = {Neuropsychopharmacology},

abstract = {Xylazine, a veterinary tranquillizer known by drug users as "Tranq", is being increasingly detected in people who overdose on opioid drugs, indicating enhanced health risk of fentanyl-xylazine mixtures. We recently found that xylazine potentiates fentanyl- and heroin-induced brain hypoxia and eliminates the rebound-like post-hypoxic oxygen increases. Here, we used oxygen sensors coupled with high-speed amperometry in rats of both sexes to explore the treatment potential of naloxone plus atipamezole, a selective α2-adrenoceptor antagonist, in reversing brain (nucleus accumbens) and periphery (subcutaneous space) hypoxia induced by a fentanyl-xylazine mixture. Pretreatment with naloxone (0.2 mg/kg, IV) fully blocked brain and peripheral hypoxia induced by fentanyl (20 μg/kg, IV), but only partially decreased hypoxia induced by a fentanyl-xylazine mixture. Pretreatment with atipamezole (0.25 mg/kg, IV) fully blocked the hypoxic effects of xylazine (1.0 mg/kg, IV), but not fentanyl. Pretreatment with atipamezole + naloxone was more potent than naloxone alone in blocking the hypoxic effects of the fentanyl-xylazine mixture. Both naloxone and naloxone + atipamezole, delivered at the peak of brain hypoxia (3 min post fentanyl-xylazine exposure), reversed the rapid initial brain hypoxia, but only naloxone + atipamezole decreased the prolonged weaker hypoxia. There were no sex differences in the effects of the different drugs and their combinations on brain and peripheral oxygen responses. Results indicate that combined treatment with naloxone and atipamezole is more effective than naloxone alone in reversing the hypoxic effects of fentanyl-xylazine mixtures. Naloxone + atipamezole treatment should be considered in preventing overdoses induced by fentanyl-xylazine mixtures in humans.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}