Grants and Contracts Details
Description
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.
Status | Active |
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Effective start/end date | 6/15/23 → 4/30/28 |
Funding
- National Institute on Drug Abuse: $512,576.00
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