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Brain Circuits Mediating Adverse Effects of Fentanyl–Xylazine: Mechanisms and Therapeutic Targets

Award Number: R01DA067016
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/15/2026
PERIOD OF PERFORMANCE END DATE: 06/30/2031

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Brain Circuits Mediating Adverse Effects of Fentanyl–Xylazine: Mechanisms and Therapeutic Targets - Project Summary/ Abstract The escalating prevalence of fentanyl adulterated with xylazine (F+X, Tranq-Dope) has intensified overdose mortality across the United States. Xylazine, a veterinary sedative acting on α2 adrenoceptors (Adra2a), prolongs fentanyl-induced respiratory depression (OIRD), brain hypoxia, and severe hypothermia— effects not seen with either drugs alone. Naloxone, the standard opioid antidote, fails to reverse these com- bined effects, underscoring the urgent need to define the neural substrates mediating F+X lethality and iden- tify novel reversal strategies. Opioids act via μ-opioid receptors (Oprm1), while xylazine acts via Adra2a. These receptors may converge on overlapping neuronal populations, where fentanyl may also modulate Adra2a sig- naling. Our published data suggest that lateral parabrachial (PB) FoxP2-expressing (PBFoxP2) neurons regulate respiration, and recent data from other labs show that they also regulate cold defense and thermogenesis. Therefore, their inhibition by F+X may suppress compensatory responses to hypoxia and hypothermia. This project is significant because it directly addresses the mechanistic basis of polysubstance over- dose lethality, focusing on PBFoxP2 neurons as critical integrators of respiratory and thermoregulatory defense. It is innovative in combining Fos‑TRAP2 genetic access to stimulus‑activated neurons, cell‑type–specific ma- nipulations in Adra2a‑floxed and FoxP2‑Cre mice, and translational testing of candidate pharmacological inter- ventions. By linking molecular receptor interactions to circuit dysfunction and therapeutic rescue, the work will establish a new framework for understanding and reversing F+X lethality, with direct implications for antidote development and NIDA’s mission to reduce overdose mortality. Central Hypothesis: F+X lethality arises from synergistic inhibition of PBFoxP2 neurons via Oprm1– Adra2a interactions, so restoring PBFoxP2 activity, blocking Adra2a, or both can reverse respiratory and ther- moregulatory depression. Aim 1: Define PB neuronal subtypes activated by hypoxia or cold and suppressed by F+X using Fos-TRAP2 profiling and in vivo calcium imaging of the PBFoxP2 and PBTRAped neurons for their responses to F+X. Aim 2: Determine the causal role of PBFoxP2 and Adra2a-expressing neurons in mediating F+X-induced OIRD and hypothermia using chemogenetic manipulations, and activity monitoring with in-vivo calcium imaging. Aim 3: Evaluate pharmacological strategies—including PBFoxP2 activation and Adra2a gene deletion—to re- verse F+X-induced respiratory depression and hypothermia. Innovation: This project is the first to dissect PBFoxP2–Adra2a interactions in polysubstance overdose, integrat- ing genetic access to stimulus-activated neurons, cell-type–specific manipulations, & translational drug testing. Impact: Findings will uncover the mechanistic basis of F+X lethality, inform development of novel reversal agents, and directly support NIDA’s mission to reduce overdose mortality from polysubstance exposure.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $508,734 )
2026	2026	BETH ISRAEL DEACONESS MEDICAL CENTER, INC.	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Drug Use and Addiction Research Programs	000	1	8/14/2026	NEW	$508,734
														Subtotal = $508,734

Grand Total All Awards = $508,734

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Brain Circuits Mediating Adverse Effects of Fentanyl–Xylazine: Mechanisms and Therapeutic Targets

Award Number: R01DA067016

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/15/2026

PERIOD OF PERFORMANCE END DATE: 06/30/2031

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