Blood-to-CNS Drug Uptake in Pain

疼痛时血液至中枢神经系统的药物摄取

• 批准号: 8307459
• 负责人: THOMAS Paul DAVIS
• 金额: --
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-08-05 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8307459
• 关键词: ABCG2 gene; Acetaminophen; Active Biological Transport; Acute; Acute Pain; Adverse effects; Affect; Alkaline Phosphatase; Amino Acid Substitution; Analgesics; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Apical; Applications Grants; Binding; Biochemical; Biological; Blood; Blood - brain barrier anatomy; Blood capillaries; Brain; Carrageenan; Carrier Proteins; Cell Nucleus; Cerebrospinal Fluid; Cerebrum; Characteristics; Chemicals; Chronic; Codeine; Comprehension; Confocal Microscopy; Cytokine Signaling; Data; Dexamethasone; Diffusion; Disease; Drug Delivery Systems; Drug Interactions; Drug Kinetics; Drug Regulations; Drug Transport; Edema; Endothelial Cells; Endothelium; Enzyme-Linked Immunosorbent Assay; Ethylene Glycols; Functional disorder; Gene Proteins; Genes; Glucocorticoids; Goals; Grant; Hour; Hyperalgesia; In Situ; Inflammation; Inflammatory; Interleukin-6; Investigation; Laboratories; Lead; Ligands; MLLT4 gene; Mediating; Mediator of activation protein; Membrane; Methodology; Methods; Modification; Molecular; Molecular Structure; Morphine; Neurons; Nuclear Receptors; OATP Transporters; Opioid; Opioid Analgesics; Opioid Peptide; P-Glycoprotein; P-Glycoproteins; Pain; Pain management; Pathway interactions; Peptides; Perfusion; Peripheral; Permeability; Pharmaceutical Preparations; Pharmacodynamics; Pharmacotherapy; Phosphorylation; Pluronics; Principal Investigator; Process; Prodrugs; Promoter Regions; Property; Protein Isoforms; Proteins; RXR; Radioactive Tracers; Radiopharmaceuticals; Receptor Activation; Regimen; Regulation; Rodent Model; Role; Route; Serum; Signal Transduction; Stereoisomer; Symptoms; System; Techniques; Testing; Therapeutic; Tight Junctions; Time; Toxic effect; Transforming Growth Factors; Variant; Western Blotting; Work; Xenobiotics; actin 2; capillary; chromatin immunoprecipitation; chronic pain; claudin 3; clinically relevant; constitutive androstane receptor; copolymer; cytokine; drug mechanism; ethylene glycol; glycosylation; halogenation; human ABCG2 protein; improved; in vivo; inflammatory pain; mRNA Expression; novel; novel strategies; novel therapeutics; occludin; pregnane X receptor; prevent; programs; protein expression; public health relevance; receptor expression; research study; response; uptake

DESCRIPTION (provided by applicant): Pain is a dominant symptom associated with acute and chronic inflammation. Pain-induced blood-brain barrier (BBB) dysfunction alters CNS delivery of analgesic drugs including opioids. A clear comprehension of biological mechanisms involved in drug transport across the BBB is essential to clarify CNS uptake of opioids and their efficacy in pain treatment. Furthermore, investigation of pathophysiological features of peripheral inflammatory pain (PIP) (i.e., changes in serum concentrations of cytokines such as IL-6 and TGF-2s) will enable an improved understanding of the regulation of drug transporters (i.e., P-glycoprotein (P-gp), Multidrug Resistance Proteins (Mrps), Breast Cancer Resistance Protein (BCRP; also known as ABCG2), organic anion transporting polypeptides (Oatps)) and/or tight junction proteins (i.e., claudin-3 and -5, occludin, ZO-1) at the BBB and how these processes relate to CNS opioid delivery. Additionally, pain management regimens may involve multiple drugs, which can lead to harmful drug-drug interactions. These drug-drug interactions may involve changes in BBB transport mechanisms associated with functional expression of nuclear receptors [i.e., pregnane-X-receptor (PXR), constitutive androstane receptor (CAR)]. The activation of PXR and/or CAR may lead to altered efficacy and/or CNS toxicity of opioids. The ability of nuclear receptors to regulate drug transport may differ between acute and chronic pain. These differences may be related to expression changes in PXR/CAR, which may be associated with variations in serum/cerebrospinal fluid cytokine levels. Our hypothesis is that changes in transport of commonly prescribed opioid analgesics and novel therapeutic opioid peptides will occur due to alterations in the functional expression of putative membrane drug transporters and tight junction proteins. We propose that these changes in transport are caused by cytokine signaling and/or activity of nuclear receptors during PIP. The aims of this grant will be investigated using a combination of in vivo methods as well as biochemical and molecular techniques established and working in our laboratory. This proposal will elucidate mechanisms that can alter CNS opioid delivery and will point to novel strategies to improve PIP treatment. PUBLIC HEALTH RELEVANCE: PIP may lead to BBB dysfunction, including changes in opioid permeability. This grant application is clinically relevant since PIP-associated changes in BBB xenobiotic permeability can be a factor in altered efficacy and CNS toxicity sometimes observed following opioid administration. This study may point to novel ways to improve CNS opioid delivery and to avoid unwanted opioid side effects during the treatment of pain.

描述（由申请人提供）：疼痛是与急性和慢性炎症有关的主要症状。疼痛引起的血脑屏障（BBB）功能障碍会改变包括阿片类药物在内的镇痛药的CNS递送。对跨BBB药物传输涉及的生物学机制的明确理解对于阐明中枢神经系统的摄取及其在疼痛治疗中的疗效至关重要。此外，研究周围炎症性疼痛（PIP）的病理生理特征（即，诸如IL-6和TGF-2S等血清浓度的变化）将使对药物转运蛋白的调节的调节有所改善，即P-糖蛋白（P-GP），多发性抗蛋白（MR HAPTRES CANCER CANCER CANCER CANCER CANCE）（MR）（MR）（MR）； ABCG2），有机阴离子运输多肽（OATPS））和/或紧密连接蛋白（即Claudin-3和-5，claudin-3和-5，occludin，ZO-1）在BBB处以及这些过程与CNS阿片类阿片类药物的相关性。此外，疼痛管理方案可能涉及多种药物，这可能导致有害的药物相互作用。这些药物相互作用可能涉及与核受体功能表达相关的BBB转运机制的变化[即孕烷-X受体受体（PXR），组成型雄激素受体（CAR）]。 PXR和/或CAR的激活可能导致阿片类药物的疗效和/或CNS毒性改变。核受体调节药物转运的能力在急性和慢性疼痛之间可能有所不同。这些差异可能与PXR/CAR的表达变化有关，这可能与血清/脑脊液细胞因子水平的变化有关。我们的假设是，由于推定的膜药物转运蛋白和紧密连接蛋白的功能表达的改变，将发生常见的阿片类镇痛药的转运和新型治疗阿片类肽的转运。我们建议这些转运的变化是由PIP期间核受体的细胞因子信号传导和/或活性引起的。这笔赠款的目的将通过体内方法以及在我们的实验室中建立和工作的生化和分子技术的组合进行研究。该建议将阐明可以改变中枢神经系统阿片类药物递送的机制，并指出改善PIP治疗的新策略。 公共卫生相关性：PIP可能导致BBB功能障碍，包括阿片类药物渗透性的变化。该赠款应用在临床上是相关的，因为在阿片类药物给药后，有时会观察到有时会观察到PIP相关的BBB异种渗透性的变化可能是改变功效和中枢神经系统毒性的因素。这项研究可能指出了改善CNS阿片类药物递送并避免疼痛治疗过程中不必要的阿片类药物副作用的新方法。