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

Neuropsychopharmacology (2023)Cite this article

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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.

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Fig. 1: Oxygen responses induced by fentanyl, xylazine, and their mixture in male and female rats.
Fig. 2: The effects of naloxone or atipamezole on oxygen responses induced by fentanyl or xylazine in male and female rats.
Fig. 3: The effects of naloxone or naloxone + atipamezole pretreatment on oxygen responses induced by fentanyl + xylazine in male and female rats.
Fig. 4: The effects of naloxone + atipamezole or naloxone alone on oxygen responses induced by fentanyl-xylazine mixture in male and female rats.

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Data availability

Raw data and the results of their primary analyses are available on request from Dr. Eugene A. Kiyatkin (NIDA-IRP, NIH; ekiyatki@intra.nida.nih.gov).

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Acknowledgements

The study was supported by the Intramural Research Program of the NIH, NIDA.

Funding

The study was supported by the Intramural Research Program of the NIH, NIDA (1ZIADA000566-12 [EAK]; 1ZIADA000434-17 [YS]).

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Authors and Affiliations

  1. Behavioral Neuroscience Branch, National Institute on Drug Abuse – Intramural Research Program, National Institutes of Health, DHHS, Baltimore, MD, 21224, USA

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

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Contributions

EAK: Conceptualization, Surgery procedures, Participation in experiments, Data analyses, Writing the manuscript; SC, MRI and MN: Conceptualization, Performance of experiments, Data analyses, Graphic work, Histological work, Review and editing the manuscript. YS: Conceptualization, Writing, and editing the manuscript.

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Correspondence to Eugene A. Kiyatkin.

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YS is an Associate (Reviewing) Editor for Neuropsychopharmacology. The other authors declare no competing interests.

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Choi, S., Irwin, M.R., Noya, M.R. et al. Combined treatment with naloxone and the alpha2 adrenoceptor antagonist atipamezole reversed brain hypoxia induced by a fentanyl-xylazine mixture in a rat model. Neuropsychopharmacol. (2023). https://doi.org/10.1038/s41386-023-01782-2

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