Increased CNS Opioid Exposure by an Acetaminophen-Induced Blood-Brain Barrier Mechanism

对乙酰氨基酚诱导的血脑屏障机制增加中枢神经系统阿片类药物暴露

基本信息

批准号：
10406995
负责人：
THOMAS Paul DAVIS
金额：
$ 56万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10406995
关键词：
ABCB1 gene Acetaminophen Acute Acute Pain Acute inflammatory pain Address Adverse drug event Adverse event Affect Americas Analgesics Animals Applications Grants Behavior Blood - brain barrier anatomy Brain Carrageenan Central Nervous System Agents Characteristics Cocaine Codeine Consumption Data Disease Dose Drug Addiction Drug Delivery Systems Drug Prescriptions Effectiveness Epidemic Female Filament Functional disorder Goals Grant Hydrocodone In Situ Individual Knowledge Laboratories Lead Ligation Measurement Mediating Methamphetamine Modeling Molecular Nerve Opioid Oxycodone Pain Pathway interactions Percocet Perfusion Permeability Pharmaceutical Preparations Pharmacologic Substance Pharmacology Positioning Attribute Proteins Public Health Rewards Role Route Signal Pathway Signal Transduction Small Interfering RNA Spinal Sprague-Dawley Rats Testing Tight Junctions Time Time Study Transforming Growth Factors Treatment-related toxicity Tylenol United States Ventilatory Depression Vicodin Work blood-brain barrier permeabilization chronic neuropathic pain chronic pain clinical effect clinically relevant clinically significant conditioned place preference experimental study improved in vivo in vivo Model inhibitor knock-down liver injury male misuse of prescription only drugs non-opioid analgesic novel occludin opioid exposure opioid misuse pain model prescription drug abuse prescription opioid prescription pain reliever protein complex protein expression protein transport receptor relationship abuse response spinal nerve pain trafficking uptake

项目摘要

PROJECT SUMMARY Over the past several years, we have studied changes in critical blood-brain barrier (BBB) tight junction (TJ) proteins (i.e., claudin-5, occludin) in response to diseases or drugs. Our work has shown that claudin-5 and occludin expression and trafficking is modulated by pain (i.e., TJ dysregulation), an effect that increases brain uptake of opioids such as codeine. Our preliminary data show that acetaminophen (APAP) can modulate expression of claudin-5 at the BBB and increase paracellular permeability (i.e., “leak”). Leak has previously been shown to occur with low dose, acute cocaine administration as well as methamphetamine. Both APAP and pain target transforming growth factor- β (TGF-β) signaling, a pathway that controls TJ expression and BBB integrity. In this grant, we hypothesize that APAP, by itself and in the setting of pain, can increase BBB “leak” and enhance CNS opioid delivery. These studies are highly significant because they will uncover mechanisms of altered opioid antinociception and adverse drug events that can occur in individuals who abuse or misuse opioids or APAP. Additionally, APAP is taken with other centrally acting drugs where “APAP leak” can lead to therapeutic toxicity. Aim 1: To investigate, in vivo, changes in TJ protein expression and trafficking at the BBB following APAP administration. We will study how APAP alters CNS effects and adverse events of opioids. We will investigate the time course of changes in transmembrane TJ protein (i.e., claudin-5, occludin) expression and trafficking and the dose-response relationship of APAP on changes in TJ protein complexes in male and female Sprague-Dawley rats (Aim 1A). We will then study the temporal relationship between CNS opioid delivery, opioid-associated antinociception, respiratory depression, and opioid-associated reward behavior (Aim 1B). Since we have shown that transforming growth factor- β (TGF-β) signaling regulates BBB integrity, we will study the role of this pathway on claudin-5 and occludin expression and trafficking (Aim 1C). Aim 2: To examine involvement of APAP on BBB integrity in pain. Using established in vivo pain models (i.e., l-carrageenan-induced acute inflammatory pain, chronic pain spinal nerve ligation), we will study the time course of APAP effects on TJ protein expression/trafficking (i.e., claudin-5, occludin) as well as on CNS opioid uptake (Aim 2A). We will demonstrate effects of single versus multiple doses of APAP on TGF-β signaling pathways in both pain models (Aim 2B). We will study how changes in CNS opioid delivery affect opioid antinociception, respiratory depression, and opioid-associated reward behavior (Aim 2C). Since we have shown that APAP increases functional expression of the critical opioid transporter P-glycoprotein, we will examine the contribution of claudin-5/occludin modulation and P-gp changes to CNS opioid delivery (Aim 2D). Our group is uniquely positioned to provide a mechanistic explanation (i.e., signaling, activity, trafficking) for adverse drug events in individuals who abuse/misuse prescription pain drugs.

项目摘要在过去的几年中，我们已经研究了关键血脑屏障（BBB）紧密连接的变化（TJ）蛋白质（即Claudin-5，occludin）响应疾病或药物。我们的工作表明Claudin-5和闭合表达和运输受疼痛（即TJ失调）调节，这种作用会增加大脑摄取阿片类药物，例如可待因。我们的初步数据表明，对乙酰氨基酚（APAP）可以调节 Claudin-5在BBB上的表达并增加细胞细胞通透性（即“泄漏”）。泄漏以前已经证明是出现低剂量，急性可卡因和甲基苯丙胺的发生。 APAP和疼痛目标转化生长因子-β（TGF-β）信号传导，这是一种控制TJ表达和BBB完整性的途径。在这笔赠款中，我们假设APAP本身和疼痛的环境可以增加BBB “泄漏”并增强CNS阿片类药物的递送。这些研究非常重要，因为它们会发现可能发生在个体中可能发生的阿片类药物抗伤害感受和不良药物事件的机制谁滥用或滥用阿片类药物或APAP。此外，与其他集中作用药物一起服用APAP “ APAP泄漏”可以导致治疗性毒性。目的1：在体内调查TJ蛋白表达和BBB的运输变化在APAP给药之后。我们将研究APAP如何改变中枢神经系统的影响和阿片类药物的不良事件。我们将研究跨膜TJ蛋白（即claudin-5，occludin）表达的时间变化的时间过程 APAP对男性和TJ蛋白复合物变化的贩运和剂量反应关系雌性Sprague-Dawley大鼠（AIM 1A）。然后，我们将研究CNS OOID之间的临时关系输送，与OIOID相关的抗伤害感受，呼吸抑郁和与OioID相关的奖励行为（AIM 1b）。由于我们已经表明，转化生长因子-β（TGF-β）信号传导调节BBB的完整性，我们将研究该途径在claudin-5和occludin表达和贩运方面的作用（AIM 1C）。目标2：检查APAP参与BBB完整性在疼痛中。使用已建立的体内疼痛模型（即L-甲rage型引起的急性炎症性疼痛，慢性脊柱神经结扎），我们将研究 APAP对TJ蛋白表达/运输的时间过程（即Claudin-5，occludin）以及CNS Oopioid摄取（AIM 2A）。我们将展示单剂量与多剂量APAP对TGF-β信号传导的影响两种疼痛模型中的途径（AIM 2B）。我们将研究CNS阿片类药物递送的变化如何影响阿片类药物抗伤害感受，呼吸道抑郁和阿片类药物相关的奖励行为（AIM 2C）。由于我们已经显示 APAP增加了关键阿片类转运蛋白P-糖蛋白的功能表达，我们将检查 Claudin-5/occludin调制和P-gp变化对中枢神经系统递送的贡献（AIM 2D）。我们的小组的位置是提供机械解释（即信号，活动，贩运）在滥用/滥用处方疼痛药物的个人中进行广告毒品事件。