Official websites use .gov

A .gov website belongs to an official government organization in the United States.

Secure .gov websites use HTTPS

A lock ( 🔒 ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

Need Help

Neurobehavioral mechanisms underlying xylazine and fentanyl co-use and withdrawal

Award Number: R01DA058933
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/15/2023
PERIOD OF PERFORMANCE END DATE: 04/30/2028

Group Awards By:

View Award Description

Neurobehavioral mechanisms underlying xylazine and fentanyl co-use and withdrawal - PROJECT SUMMARY/ABSTRACT Prescription and illicit opioid use have risen to a public health crisis, with the landscape shifting to fentanyl use. Given that fentanyl is 100-fold more potent than morphine, its use is associated with a higher risk of fatal overdose. Naloxone (Narcan) reverses opioid overdose and precipitates withdrawal. However, recent reports indicate that xylazine, an anesthetic that is increasingly detected in accidental fentanyl overdose deaths, has become a highly sought-after adulterant that can prolong both the fentanyl “high” and the onset of fentanyl withdrawal, as well as precipitate resistance to naloxone in the reversal of overdose. Despite this, no systematic studies to date have evaluated the neurobehavioral mechanistic contributors to these effects. While opioid pharmacological mechanisms of action have been studied, it is not clear how the addition of xylazine to fentanyl inhibits the actions of naloxone, as either alone does not have this action. Excitingly, we have possibly discovered the mechanisms of how xylazine combined with fentanyl causes resistance to naloxone using our State-of-the- Art PamGene PamStation technology that measures hundreds of kinase activities in a single sample. We show preliminary data for the signaling pathways in the nucleus accumbens core (NAcore) that are hyper- or hypo- active, which gives us numerous potential targets for reversing naloxone resistance and xylazine’s effects on fentanyl self-administration (SA). We hypothesize that the xylazine-fentanyl combination activates non- canonical pathways that reduce consumption and prolong the onset of fentanyl withdrawal signs. Our objective here is to uncover these unknown mechanisms using our PamGene technology and determine how these impact neurocircuitry and behavior. Therefore, we will test these in our following Aims: 1) Determine how xylazine impacts the effects of fentanyl, 2) Determine viable therapeutic targets to resensitize fentanyl withdrawal following the escalation of xylazine-fentanyl SA, and 3) Determine neural circuits altering the NAcore and ventral tegmental area (VTA) kinomes following the escalation of xylazine-fentanyl SA and if these underlie naloxone resistance. We will map the active kinome of the NAcore and VTA following xylazine-fentanyl co-use and will test novel treatment targets that we find are changed via our extensive analysis. We will further test if these neural circuits contribute to co-use-induced alterations in targets that we have identified from our PamGene analysis, and thus we will determine if suppressing these circuits may enhance the actions of naloxone and restore neural targets altered by xylazine-fentanyl co-use (measured via kinome analysis). Together, these hypothesis-driven studies will markedly enhance our understanding of the neurobehavioral mechanisms underlying xylazine-fentanyl polysubstance use and withdrawal and will likely reveal novel treatment strategies for reversing the xylazine-fentanyl-induced naloxone inefficacy.


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 = $487,408 )
2026	2026	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE	LEXINGTON	KY	40526	FAYETTE	USA	Drug Use and Addiction Research Programs	000	4	4/29/2026	NON-COMPETING CONTINUATION	$487,408
														Subtotal = $487,408

Issue Date FY: 2025 ( Subtotal = $496,587 )
2025	2025	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE	LEXINGTON	KY	40526	FAYETTE	USA	Drug Use and Addiction Research Programs	000	3	4/17/2025	NON-COMPETING CONTINUATION	$496,587
														Subtotal = $496,587

Issue Date FY: 2024 ( Subtotal = $502,057 )
2024	2024	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE	LEXINGTON	KY	40526	FAYETTE	USA	Drug Use and Addiction Research Programs	000	2	4/23/2024	NON-COMPETING CONTINUATION	$502,057
														Subtotal = $502,057

Issue Date FY: 2023 ( Subtotal = $512,576 )
2023	2023	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Drug Use and Addiction Research Programs	000	1	6/9/2023	NEW	$512,576
														Subtotal = $512,576

Grand Total All Awards = $1,998,628

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Neurobehavioral mechanisms underlying xylazine and fentanyl co-use and withdrawal

Award Number: R01DA058933

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/15/2023

PERIOD OF PERFORMANCE END DATE: 04/30/2028

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer