Unregulated use of fentanyl and overdose deaths have increased dramatically in recent years, and this trend was made more alarming when authorities found fentanyl laced with the animal tranquilizer xylazine.
May 16 2024University of North Carolina at Chapel Hill Some addiction specialists and public health officials feared the added xylazine would impede the fast-acting effects of the drug naloxone, which can effectively treat patients experiencing respiratory depression – a serious side effect of opioid use that can lead to death.
"Many people thought xylazine operated exclusively through a different mechanism in the nervous system," said McElligott, who is also a member of the UNC Bowles Center for Alcohol Studies. "But because we show xylazine is an agonist at kappa opioid receptors in the brain and body, in addition to acting at other targets, we may have gleaned insight into why withdrawal from the combination of fentanyl and xylazine is so harsh.
"I was blown away because xylazine is what many scientists use to anesthetize animals for lab experiments usually in combination with ketamine, and large and small animal veterinarians use it as a sedative as well," McElligott said. "We were interested because early on we read case reports that withdrawal from fentanyl/xylazine is particularly bad, and we study the effects of withdrawal, how withdrawal changes brain circuits and promotes the continued use of drugs and alcohol.
Related StoriesMcElligott and Bedard began thinking through the possibilities. Xylazine is known to target α2- adrenergic receptors throughout the nervous system, and so they thought maybe naloxone was somehow bumping xylazine off those receptors to promote withdrawal. That seemed unlikely, she said, and they performed experiments with an α2-adrenergic receptor inhibitor that did not resemble what they saw with naloxone.
Roth's lab wound up running a full profile on xylazine, including a slew of assays to be sure xylazine was activating kappa opioid receptors in addition to adrenergic receptors. It was.
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