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Neurobehavioral mechanisms underlying xylazine and fentanyl co-use and withdrawal

赛拉嗪和芬太尼共同使用和戒断的神经行为机制

基本信息

批准号：
10737712
负责人：
Cassandra D Gipson-Reichardt
金额：
$ 51.26万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-15 至 2028-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10737712
关键词：
Accidents Adrenergic Agents Affect Agonist Anesthetics Behavior Biological Assay Brain CSF1R gene Clinical Consumption Data Disinhibition Dopamine Dose Drug Combinations Drug usage EGF gene Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Event FDA approved Fentanyl Future Heroin Hyperactivity Impact evaluation Individual Maps Measures Morphine Naloxone Neurobiology Nucleus Accumbens Opioid Opioid Receptor Overdose reversal Pathway interactions Pattern Pharmaceutical Preparations Phenotype Phosphotransferases Precipitation Public Health Rattus Reporting Research Resistance Rewards Sampling Self Administration Signal Pathway Signal Transduction Technology Testing Therapeutic Urine Ventral Tegmental Area Western Blotting Withdrawal Xylazine behavioral phenotyping fentanyl overdose fentanyl self-administration fentanyl use genetic manipulation high risk high risk population illicit opioid improved lofexidine manufacture neural neural circuit neurobehavioral neuromechanism novel opioid overdose opioid use opioid withdrawal overdose death pharmacologic polysubstance use prescription opioid prevent receptor response therapeutic target treatment strategy

项目摘要

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.

项目总结/文摘