PROJECT SUMMARY
Since the mid-2010s, the US has experienced a sharp rise in drug overdose fatalities driven by the emergence
of the ultra-potent synthetic opioid fentanyl within the illicit drug supply. Recently, evidence derived from drug
seizures, epidemiological surveys, and clinical case reports show that fentanyl is being increasingly adulterated
with xylazine, an alpha-2 adrenergic receptor agonist approved for veterinary use as a sedative and analgesic.
According to anecdotal reports, xylazine is a desirable adulterant because it prolongs the otherwise brief
euphoria produced by fentanyl. However, fentanyl-xylazine mixtures have also been associated with severe
health risks as compared to fentanyl alone, including potentiated drug-induced hypoxia and enhanced resistance
to the opioid receptor antagonist naloxone. Collectively, these interactive effects likely contribute to the greater
overall risk for irreversible overdose and lethality recently observed in preclinical studies and clinical case reports.
This has led the US Government to designate fentanyl-xylazine mixtures as a “highly toxic chemical of concern”
and an “emerging threat” requiring rapid response. Alpha-2 receptor activation reduces central norepinephrine
levels, resulting in a physiological toxidrome resembling opioid exposure that includes respiratory depression,
bradycardia, and hypotension. However, the precise impact of fentanyl-xylazine mixtures on cardiorespiratory
function has not been examined, leaving unresolved the specific manner by which lethality might be prevented
in an emergency medical setting. Furthermore, xylazine-induced potentiation of fentanyl’s subjective effects has
not yet been evaluated in animal models, and thus the pharmacological mechanisms underlying this interactive
effect remain poorly understood. In this proposal, we will test the hypothesis that xylazine enhances both the
cardiorespiratory-depressant and subjective effects of fentanyl, and that dual antagonism of opioid receptors and
alpha-2 adrenergic receptors prevents the effects of combined fentanyl-xylazine exposure on these measures in
rats. In Aim 1, we will use telemetry and plethysmography to comprehensively characterize xylazine’s impacts
on fentanyl-induced changes in heart rate, blood pressure, core temperature, and respiration. In Aim 2, we will
determine whether xylazine intensifies and/or prolongs the interoceptive-stimulus effects of fentanyl using drug
discrimination procedures. Finally, in both Aims, we will test whether the effects of fentanyl-xylazine mixtures are
fully antagonized by co-administration of naloxone and the highly-selective alpha-2 receptor antagonist
atipamezole, an FDA-approved veterinary medication that safely and effectively reverses the sedative and
cardiorespiratory-depressant effects of alpha-2 receptors agonists in humans. If successful, these studies will
identify the receptor targets that mediate both the desirable and harmful effects of fentanyl-xylazine mixtures,
paving the way for the rapid development of effective overdose rescue medications and much-needed treatments
for fentanyl-xylazine misuse, potentially saving thousands of lives.
