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

• 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
• 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

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.

项目概要/摘要 处方药和非法阿片类药物的使用已上升为公共卫生危机，芬太尼的使用也随之发生变化。 鉴于芬太尼的效力比吗啡强 100 倍，因此使用芬太尼会导致更高的致命风险 过量。纳洛酮（Narcan）可逆转阿片类药物过量并加速戒断。然而，最近的报道 表明甲苯噻嗪是一种麻醉剂，在芬太尼过量服用意外死亡事件中越来越多地被发现， 成为一种备受追捧的掺假剂，可以延长芬太尼的“快感”和芬太尼的起效时间 戒断，以及在逆转用药过量时加速对纳洛酮的抵抗。尽管如此，还没有系统的 迄今为止的研究已经评估了这些影响的神经行为机制因素。虽然阿片类药物 药理作用机制已被研究，尚不清楚甲苯噻嗪如何添加到芬太尼中 抑制纳洛酮的作用，因为单独使用任何一种都没有这种作用。令人兴奋的是，我们可能发现 赛拉嗪与芬太尼联合使用如何导致纳洛酮耐药的机制 Art PamGene PamStation 技术可测量单个样品中的数百种激酶活性。我们展示 伏隔核核心 (NAcore) 信号传导通路的初步数据 活性，这为我们提供了许多逆转纳洛酮耐药性和赛拉嗪对 芬太尼自我给药（SA）。我们假设甲苯噻嗪-芬太尼组合会激活非 减少芬太尼消耗并延长芬太尼戒断症状发作的典型途径。我们的目标 这里是使用我们的 PamGene 技术揭示这些未知机制并确定它们如何影响 神经回路和行为。因此，我们将在以下目标中测试这些：1) 确定甲苯噻嗪如何 影响芬太尼的效果，2) 确定可行的治疗靶点以重新提高芬太尼戒断的敏感性 随着甲苯噻嗪-芬太尼 SA 的升级，以及 3) 确定改变 NAcore 和腹侧的神经回路 赛拉嗪-芬太尼 SA 升级后的被盖区 (VTA) 激酶组，以及这些是否是纳洛酮的基础 反抗。我们将绘制赛拉嗪-芬太尼共同使用后 NAcore 和 VTA 的活性激酶组图，并将 通过我们的广泛分析，测试我们发现改变的新治疗目标。我们将进一步测试这些是否 神经回路有助于我们从 PamGene 中识别出的目标的共同使用引起的改变 分析，因此我们将确定抑制这些回路是否可以增强纳洛酮和 恢复因甲苯噻嗪和芬太尼共同使用而改变的神经靶标（通过激酶组分析测量）。在一起，这些 假设驱动的研究将显着增强我们对神经行为机制的理解 潜在的甲苯噻嗪-芬太尼多物质使用和戒断，可能会揭示新的治疗策略 用于逆转甲苯噻嗪-芬太尼引起的纳洛酮无效。