Blood Brain Barrier Changes Induced by Pain

描述（由申请人提供）：每年有超过1.16亿美国人遭受疼痛的折磨，在医疗和生产力损失方面的花费估计为6350亿美元。治疗疼痛（急性/术后和慢性）通常涉及阿片类镇痛药。我们已经表明，外周炎性疼痛（PIP）促进血脑屏障功能障碍，其特征是外排转运蛋白和紧密连接（TJ）蛋白的表达和定位改变，以及细胞旁通透性（即渗漏）增加。这些变化的临床意义在于改变了阿片类镇痛药的脑摄取。在这一更新中，我们提出了一个新的假设，即PIP期间血脑屏障功能障碍，改变了阿片类镇痛药的细胞旁通透性和中枢神经系统递送，可以通过病理诱导的P-糖蛋白（Pgp）和TJ蛋白occludin和cludin的运输改变来调节，这些蛋白对TJ寡聚蛋白组装的形成和完整性至关重要。有两个具体目标

DESCRIPTION (provided by applicant): Pain afflicts over 116 million Americans annually and costs an estimated $635 billion dollars in medical treatments and lost productivity. The treatment of pain (both acute/post-surgical and chronic) often involves opioid analgesics. We have shown that peripheral inflammatory pain (PIP) promotes BBB dysfunction characterized by changes in expression and localization of efflux transporter and tight junction (TJ) proteins as well as increased paracellular permeability (i.e., leak). The clinical relevance of these changes i altered brain uptake of opioid analgesics. In this renewal, we propose to test the novel hypothesis that BBB dysfunction during PIP, which alters paracellular permeability and CNS delivery of opioid analgesics, can be modulated by therapeutic targeting of pathology-induced changes in trafficking of P- glycoprotein (Pgp) and of TJ proteins occludin and claudins that are critical to the formation and integrity of TJ oligomeric protein assemblies. Two specific aims will test this hypothesis. Aim 1: To determine how PIP-induced changes in Pgp trafficking result in increased Pgp drug efflux activity. In this aim, we will identify components of Pgp storage compartment(s) isolated from cerebral microvessels (Aim 1A). We will also correlate changes in Pgp opioid efflux activity with changes in Pgp trafficking over a 1-72 hr time course (one-hit or rechallenge) (Aim 1B). Since production of reactive oxygen species (ROS) is a critical component of pain/inflammation, we will evaluate the effect of administration of TEMPOL (i.e., 4-hydroxy-2,2,6,6-tetramethylpiperidine-N- oxyl), a ROS scavenger, on Pgp trafficking as well as brain uptake and analgesic efficacy of opioids over a 1-72 hr time course of PIP (one-hit or rechallenge) (Aim 1C). Aim 2: To examine how PIP-induced changes in TJ protein trafficking modulate paracellular BBB permeability. In this aim, we will identify proteins associated with TJs isolated from cerebral microvessels (Aim 2A). We will also correlate changes in paracellular BBB permeability with changes in protein-protein interactions that cause changes in intracellular trafficking of occludin and claudins over a 1-72 hr time course of PIP (one-hit or rechallenge) (Aim 2B). We will then evaluate the effect of TEMPOL administration on occludin/claudin trafficking, on BBB paracellular permeability to codeine and codeine efficacy over a 1-72 hr time course of PIP (one-hit or rechallenge). (Aim 2C). Our goal in this renewal is to discover novel therapeutic targets for treating both pain and pain-induced BBB dysfunction by defining the role of protein trafficking in promoting changes in BBB structure/function that lead to altered CNS drug delivery during PIP.