PPAR Inhibition of Spinal Pain Transmission

PPAR 抑制脊髓疼痛传播

• 批准号: 8391225
• 负责人: BRADLEY K. TAYLOR
• 金额: $ 30.72万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-18 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8391225
• 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

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？）是一个很好的特点，作为一个关键的目标， 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。 背角的mRNA和蛋白质。此外，我们证明，机械和热 鞘内给药可迅速降低与炎症或神经损伤相关的超敏反应 罗格列酮（一种TZD）和15 d-PGJ 2（一种内源性PPAR <$配体）的剂量和PPAR <$依赖性 的方式，并通过全身给药吡格列酮，BBB渗透，FDA批准的配体。中央 该建议的假设是，背角中的过氧化物酶体增殖体激活受体的配体依赖性激活减少了损伤- 诱导脊髓神经元和神经胶质细胞的激活，然后抑制炎症和炎症反应的行为体征， 神经性疼痛本申请的目的是鉴定PPAR-L1的潜在机制。 介导的炎症性或神经性疼痛的抑制，重点是吡格列酮。我们的长期目标是 研究计划是利用PPAR信号的治疗潜力来缓解人类的慢性疼痛。 目的1将检验过氧化物酶体增殖物激活受体激动剂减少异常性疼痛和痛觉过敏的假设。我们将使用 药理学试剂和神经系统特异性PPAR <$缺失突变体，以确定 脊髓中的过氧化物酶体增殖物激活受体信号传导对慢性疼痛的诱导和维持。首先，我们将确定 单次鞘内或全身给予吡格列酮和15 d-PGJ 2是否减少了 炎性和神经性疼痛。我们预测，它们的镇痛作用将被过氧化物酶体增殖物激活受体阻断。 对手。其次，我们将确定是否长期鞘内或口服给予PPAR激动剂， 在组织或神经损伤之前或之后开始，减少炎性和神经性疼痛的行为体征。 第三，我们预测，抗异常性疼痛的行动将不会发生在小鼠与神经元特异性过氧化物酶体增殖物激活物受体基因敲低。 AIM 2将检验这一假设，即过氧化物酶体增殖物激活受体配体减少损伤诱导的神经元激活， 背角的小胶质细胞损伤大鼠的躯体感觉刺激诱导 即早基因c-fos存在于脊髓背角浅层。我们预测， 吡格列酮将减少炎症和神经损伤诱导的Fos免疫反应神经元的表达， 以及OX-42的表达，OX-42是小胶质细胞活化的标志物。 目的3将测试内源性过氧化物酶体增殖物激活受体系统紧张性抑制异常性疼痛的假设。一是 确定在疼痛过程中激活的神经元和/或神经胶质中是否发生PPAR？表达。第二，在一个 目的1-2的延伸，我们将确定受体拮抗剂和基因缺失是否增加异常性疼痛 和神经元/神经胶质活化。如果是肯定的，那么我们将确定PPAR信号元件是否共同作用， 与异常性疼痛有关。在神经损伤或持续性炎症后的不同时间，我们将评估： 和A）PPAR <$mRNA和蛋白质; B）磷酸化的PPAR <$;和C）LC/MS/MS的15 d-PGJ 2水平。