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.

项目概要在过去的几年里，我们研究了临界血脑屏障（BBB）紧密连接的变化 (TJ) 蛋白（即claudin-5、occludin）对疾病或药物的反应我们的工作表明，claudin-5 和 occludin 的表达和运输受到疼痛（即 TJ 失调）的调节，这种作用会增加大脑我们的初步数据表明，对乙酰氨基酚 (APAP) 可以调节阿片类药物的摄取。 Claudin-5 在 BBB 的表达并增加细胞旁通透性（即“泄漏”）。显示低剂量、急性可卡因以及甲基苯丙胺给药都会发生 APAP 和疼痛。靶向转化生长因子-β (TGF-β) 信号传导，这是控制 TJ 表达和 BBB 完整性的途径。在这笔资助中，我们认为 APAP 本身以及在疼痛的情况下可以增加 BBB “泄漏”并增强中枢神经系统阿片类药物的输送非常重要，因为它们将揭示这一点。阿片类药物镇痛机制和个体可能发生的药物不良事件滥用或误用阿片类药物或 APAP 的人另外，APAP 与其他中枢作用药物一起服用。其中“APAP 泄漏”可能导致治疗毒性。目标 1：体内研究 BBB 上 TJ 蛋白表达和运输的变化 APAP 给药后，我们将研究 APAP 如何改变阿片类药物的中枢神经系统作用和不良事件。我们将研究跨膜 TJ 蛋白（即claudin-5、occludin）表达变化的时间过程 APAP 对男性和女性 TJ 蛋白复合物变化的运输和剂量反应关系雌性 Sprague-Dawley 大鼠（目标 1A）然后我们将研究中枢神经系统阿片类药物之间的时间关系。递送、阿片类药物相关的反感、呼吸抑制和阿片类药物相关的奖励行为（Aim 由于我们已经证明转化生长因子-β (TGF-β) 信号调节 BBB 完整性，因此我们将研究该通路对claudin-5 和occludin 表达和运输的作用（目标1C）。目标 2：利用已确定的体内疼痛来检查 APAP 对疼痛中 BBB 完整性的影响。模型（即左旋角叉菜胶引起的急性炎性疼痛、脊髓神经结扎慢性疼痛），我们将研究 APAP 对 TJ 蛋白表达/运输（即claudin-5、occludin）以及 CNS 的影响的时间进程我们将证明单剂量与多剂量 APAP 对 TGF-β 信号传导的影响。我们将研究中枢神经系统阿片类药物输送的变化如何影响阿片类药物。反感、呼吸抑制和阿片类药物相关的奖励行为（目标 2C）。 APAP 增加了关键阿片转运蛋白 P-糖蛋白的功能表达，我们将检查 claudin-5/occludin 调节和 P-gp 变化对中枢神经系统阿片类药物输送的贡献 (Aim 2D)。我们的团队具有独特的优势，可以提供机械解释（即信号、活动、贩运）用于滥用/误用处方止痛药的个人的不良药物事件。