PPAR Inhibition of Spinal Pain Transmission

PPAR 抑制脊髓疼痛传播

基本信息

批准号：
8197774
负责人：
BRADLEY K. TAYLOR
金额：
$ 31.83万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-12-18 至 2013-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8197774
关键词：
9-deoxy-delta-9-prostaglandin D2 Adverse effects Agonist Analgesics Antidiabetic Drugs Astrocytes Basic Science Behavior Behavioral Chronic Clinical Treatment Clinical Trials Cobalt Diabetes Mellitus Dose FDA approved FOS gene Genetic Goals Healthcare Human Hyperalgesia Hypersensitivity Immediate-Early Genes Immunohistochemistry Inflammation Inflammatory Injury Lead Ligands Maintenance Mass Spectrum Analysis Mechanics Mediating Messenger RNA Microglia Mus Nervous system structure Neurodegenerative Disorders Neuroglia Neurons Oral Administration PPAR gamma Pain Pain management Peripheral Peripheral nerve injury Peroxisome Proliferator-Activated Receptors Pioglitazone Protein Isoforms Proteins Rattus Receptor Inhibition Receptor Signaling Regulation Research Signal Transduction Spinal Spinal Cord Stimulus System Testing Therapeutic Thiazolidinediones Time Tissues Transgenic Mice Translations Western Blotting allodynia chronic pain dorsal horn inflammatory neuropathic pain inflammatory pain injured innovation liquid chromatography mass spectrometry mutant nerve injury novel painful neuropathy programs public health relevance receptor research study rosiglitazone somatosensory transmission process

项目摘要

PROJECT DESCRIPTION Peroxisome proliferator-activated receptor gamma (PPAR ¿) is well-characterized as a key target of the thiazolinedione (TZD) class of anti-diabetic drugs. Our preliminary results describe the existence of PPAR ¿ mRNA and protein in the dorsal horn. Furthermore, we demonstrate that the mechanical and thermal hypersensitivity associated with inflammation or nerve injury was rapidly reduced by intrathecal administration of rosiglitazone (a TZD) and 15d-PGJ2 (an endogenous PPAR ¿ ligand) in a dose- and PPAR ¿-dependent manner, and by systemic administration of pioglitazone, a BBB-permeant, FDA-approved ligand. The central hypothesis of this proposal is that ligand-dependent activation of PPAR¿ in the dorsal horn decreases injury- induced activation of spinal neurons and glia that then dampens behavioral signs of inflammatory and neuropathic pain. The objective of the present application is to identify the mechanisms underlying PPAR- mediated inhibition of inflammatory or neuropathic pain, with a focus on pioglitazone. The long-term goal of our research program is to harness the therapeutic potential of PPAR signaling to alleviate chronic pain in humans. AIM 1 will test the hypothesis that PPAR ¿ agonists reduce allodynia and hyperalgesia. We will use pharmacological agents and nervous system-specific PPAR ¿ deletion mutants to determine the contribution of PPAR ¿ signaling in the spinal cord to the induction and maintenance of chronic pain. First, we will determine whether single intrathecal or systemic administration of pioglitazone and 15d-PGJ2 reduces behavioral signs of inflammatory and neuropathic pain. We predict that their analgesic actions will be blocked with PPAR ¿ antagonists. Second, we will determine whether chronic intrathecal or oral administration of PPAR ¿ agonists, begun before or after tissue or nerve injury, reduces behavioral signs of inflammatory and neuropathic pain. Third, we predict that anti-allodynic actions will not occur in mice with neuron-specific PPAR ¿ knockdown. AIM 2 will test the hypothesis that PPAR ¿ ligands reduce injury-induced activation of neurons and microglia in the dorsal horn. Somatosensory stimulation of injured rats induces the expression of the immediate early gene, c-fos, in the superficial laminae of the dorsal horn. We predict that intrathecal pioglitazone will reduce inflammation- and nerve injury-induced expression of Fos immunoreactive neurons, as well as the expression of OX-42, a marker of microglia activation. AIM 3 will test the hypothesis that endogenous PPAR ¿ systems tonically inhibit allodynia. First, we will determine if PPAR¿ expression occurs in neurons and/or glia that are activated during pain. Second, in an extension of Aims 1-2, we will determine whether receptor antagonists and genetic deletion increase allodynia and neuronal/glial activation. If affirmative, then we will determine whether the PPAR¿ signaling elements co- vary with allodynia. At various times after nerve injury or persistent inflammation, we will evaluate: behavior and A) PPAR ¿ mRNA and protein; B) phosphorylated PPAR ¿; and C) 15d-PGJ2 levels with LC/MS/MS.

项目描述过氧化物酶体增殖物激活受体 γ (PPAR¿) 被广泛认为是噻唑啉二酮 (TZD) 类抗糖尿病药物我们的初步结果描述了 PPAR 的存在 ¿ 此外，我们还证明了背角中的 mRNA 和蛋白质。通过鞘内给药可迅速减少与炎症或神经损伤相关的超敏反应罗格列酮（TZD）和 15d-PGJ2（一种内源性 PPAR 配体）在剂量和 PPAR ¿依赖的方式，并通过全身施用吡格列酮（一种 BBB 渗透性、 FDA 批准的配体）。该提议的假设是 PPAR 的配体依赖性激活在背角减少伤害- 诱导脊髓神经元和神经胶质细胞的激活，从而抑制炎症和神经胶质细胞的行为迹象本申请的目的是确定PPAR-的潜在机制。介导的炎症或神经性疼痛的抑制，重点是吡格列酮我们的长期目标。研究计划旨在利用 PPAR 信号传导的治疗潜力来减轻人类的慢性疼痛。 AIM 1 将检验以下假设：PPAR ¿我们将使用激动剂减少异常性疼痛和痛觉过敏。药物制剂和神经系统特异性 PPAR缺失突变体以确定的贡献 PPAR??首先，我们将确定脊髓中诱导和维持慢性疼痛的信号。吡格列酮和 15d-PGJ2 的单次鞘内给药或全身给药是否会减少行为症状我们预测它们的镇痛作用将被 PPAR 阻断。其次，我们将确定 PPAR 是长期鞘内给药还是口服给药？激动剂，在组织或神经损伤之前或之后开始，可以减少炎症和神经性疼痛的行为症状。第三，我们预测具有神经元特异性 PPAR 的小鼠不会出现抗异常疼痛作用 ¿击倒。 AIM 2 将检验以下假设：PPAR ¿配体减少损伤诱导的神经元激活受伤大鼠背角小胶质细胞的体感刺激诱导表达。立即早期基因，c-fos，位于背角浅层，我们预测鞘内。吡格列酮将减少炎症和神经损伤诱导的 Fos 免疫反应性神经元的表达，如以及小胶质细胞激活标志物 OX-42 的表达。 AIM 3 将检验内源性 PPAR ¿首先，我们将系统强直抑制异常性疼痛。确定 PPAR 是否其次，表达发生在疼痛期间激活的神经元和/或神经胶质细胞中。目标1-2的延伸，我们将确定受体拮抗剂和基因缺失是否会增加异常性疼痛如果是的话，我们将确定 PPAR 是否激活。信号元件共因异常性疼痛而异。在神经损伤或持续炎症后的不同时间，我们将评估：行为。和 A) PPAR ¿ mRNA 和蛋白质；B) 磷酸化 PPAR ¿ ；和C) LC/MS/MS 的15d-PGJ2 水平。