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:
- 金额:$ 51.26万
- 依托单位:
- 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:
- 关键词:AccidentsAdrenergic AgentsAffectAgonistAnestheticsBehaviorBiological AssayBrainCSF1R geneClinicalConsumptionDataDisinhibitionDopamineDoseDrug CombinationsDrug usageEGF geneEpidermal Growth Factor ReceptorEpidermal Growth Factor Receptor Tyrosine Kinase InhibitorEventFDA approvedFentanylFutureHeroinHyperactivityImpact evaluationIndividualMapsMeasuresMorphineNaloxoneNeurobiologyNucleus AccumbensOpioidOpioid ReceptorOverdose reversalPathway interactionsPatternPharmaceutical PreparationsPhenotypePhosphotransferasesPrecipitationPublic HealthRattusReportingResearchResistanceRewardsSamplingSelf AdministrationSignal PathwaySignal TransductionTechnologyTestingTherapeuticUrineVentral Tegmental AreaWestern BlottingWithdrawalXylazinebehavioral phenotypingfentanyl overdosefentanyl self-administrationfentanyl usegenetic manipulationhigh riskhigh risk populationillicit opioidimprovedlofexidinemanufactureneuralneural circuitneurobehavioralneuromechanismnovelopioid overdoseopioid useopioid withdrawaloverdose deathpharmacologicpolysubstance useprescription opioidpreventreceptorresponsetherapeutic targettreatment 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
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Cassandra D Gipson-Reichardt其他文献
Cassandra D Gipson-Reichardt的其他文献
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{{ truncateString('Cassandra D Gipson-Reichardt', 18)}}的其他基金
Contributions of Progestins Independently and Interactively with Contraceptive Estrogen to Nicotine Use
孕激素独立和与避孕雌激素相互作用对尼古丁使用的贡献
- 批准号:
10710219 - 财政年份:2022
- 资助金额:
$ 51.26万 - 项目类别:
Contributions of Progestins Independently and Interactively with Contraceptive Estrogen to Nicotine Use
孕激素独立和与避孕雌激素相互作用对尼古丁使用的贡献
- 批准号:
10592661 - 财政年份:2022
- 资助金额:
$ 51.26万 - 项目类别:
Neuroinflammatory and glutamatergic mechanisms of nicotine seeking
寻求尼古丁的神经炎症和谷氨酸机制
- 批准号:
10214266 - 财政年份:2020
- 资助金额:
$ 51.26万 - 项目类别:
Glutamergic Mechanisms in Opioid and Cocaine Co-Use
阿片类药物和可卡因共同使用的谷氨酸机制
- 批准号:
10669480 - 财政年份:2020
- 资助金额:
$ 51.26万 - 项目类别:
Neuroinflammatory and glutamatergic mechanisms of nicotine seeking
寻求尼古丁的神经炎症和谷氨酸机制
- 批准号:
10231269 - 财政年份:2020
- 资助金额:
$ 51.26万 - 项目类别:
Glutamergic Mechanisms in Opioid and Cocaine Co-Use
阿片类药物和可卡因共同使用的谷氨酸机制
- 批准号:
9978489 - 财政年份:2020
- 资助金额:
$ 51.26万 - 项目类别:
Neuroinflammatory and glutamatergic mechanisms of nicotine seeking
寻求尼古丁的神经炎症和谷氨酸机制
- 批准号:
10684702 - 财政年份:2020
- 资助金额:
$ 51.26万 - 项目类别:
Glutamergic Mechanisms in Opioid and Cocaine Co-Use
阿片类药物和可卡因共同使用的谷氨酸机制
- 批准号:
10264811 - 财政年份:2020
- 资助金额:
$ 51.26万 - 项目类别:
Neuroinflammatory and glutamatergic mechanisms of nicotine seeking
寻求尼古丁的神经炎症和谷氨酸机制
- 批准号:
10684352 - 财政年份:2020
- 资助金额:
$ 51.26万 - 项目类别:
Neuroinflammatory and glutamatergic mechanisms of nicotine seeking
寻求尼古丁的神经炎症和谷氨酸机制
- 批准号:
10899797 - 财政年份:2020
- 资助金额:
$ 51.26万 - 项目类别:
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