PPAR Inhibition of Spinal Pain Transmission

PPAR 抑制脊髓疼痛传播

• 批准号: 7992377
• 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
• 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/7992377
• 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

DESCRIPTION (provided by applicant): Peroxisome proliferator-activated receptor gamma (PPAR 3) is well-characterized as a key target of the thiazolinedione (TZD) class of anti-diabetic drugs. Our preliminary results describe the existence of PPAR 3 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 3 ligand) in a dose- and PPAR 3-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 PPAR3 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 3 agonists reduce allodynia and hyperalgesia. We will use pharmacological agents and nervous system-specific PPAR 3 deletion mutants to determine the contribution of PPAR 3 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 3 antagonists. Second, we will determine whether chronic intrathecal or oral administration of PPAR 3 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 3 knockdown. AIM 2 will test the hypothesis that PPAR 3 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 3 systems tonically inhibit allodynia. First, we will determine if PPAR3 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 PPAR3 signaling elements co- vary with allodynia. At various times after nerve injury or persistent inflammation, we will evaluate: behavior and A) PPAR 3 mRNA and protein; B) phosphorylated PPAR 3; and C) 15d-PGJ2 levels with LC/MS/MS. PUBLIC HEALTH RELEVANCE Chronic pain management is a major scientific and health care challenge, as current analgesic drugs rarely provide sufficient efficacy in the absence of serious side effects. We propose that ligands for peroxisome proliferator-activated receptor gamma (PPAR 3), such as rosiglitazone and pioglitazone, represent a novel class of analgesic / anti-allodynic compounds. These conceptually innovative experiments are important and timely because TZDs are commercially available for diabetes and are in clinical trials for CNS neurodegenerative diseases. Thus, confirmation of our hypothesis could lead to rapid translation to the clinical treatment of chronic pain.

描述（由申请方提供）：过氧化物酶体增殖物激活受体γ（PPAR 3）被充分表征为噻唑啉二酮（TZD）类抗糖尿病药物的关键靶点。我们的初步结果描述了PPAR 3 mRNA和蛋白在背角的存在。此外，我们证明了与炎症或神经损伤相关的机械和热超敏反应可通过鞘内注射罗格列酮（TZD）和15 d-PGJ 2（内源性PPAR 3配体）以剂量和PPAR 3依赖性方式迅速降低，并通过全身注射吡格列酮（BBB渗透性，FDA批准的配体）降低。该提议的中心假设是，背角中的PPAR 3的配体依赖性活化降低了脊髓神经元和神经胶质的损伤诱导的活化，然后抑制炎性和神经性疼痛的行为体征。本申请的目的是鉴定潜在的PPAR介导的炎性或神经性疼痛抑制的机制，重点是吡格列酮。我们研究计划的长期目标是利用PPAR信号的治疗潜力来缓解人类的慢性疼痛。目的1将检验PPAR 3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的PPAR 3缺失突变体来确定脊髓中的PPAR 3信号传导对慢性疼痛的诱导和维持的贡献。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是否会减少炎症和神经性疼痛的行为体征。我们预测它们的镇痛作用将被PPAR 3拮抗剂阻断。第二，我们将确定在组织或神经损伤之前或之后开始的慢性鞘内或口服给予PPAR 3激动剂是否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PPAR 3敲低。目的2将测试的假设，过氧化物酶体增殖物激活受体3配体减少损伤诱导的激活的神经元和小胶质细胞在背角。躯体感觉刺激损伤大鼠诱导即刻早期基因c-fos在背角浅层表达。我们预测，鞘内吡格列酮将减少炎症和神经损伤诱导的Fos免疫反应神经元的表达，以及OX-42（小胶质细胞活化的标志物）的表达。目的3将检验内源性PPAR 3系统张力性抑制异常性疼痛的假设。首先，我们将确定PPAR 3表达是否发生在疼痛过程中激活的神经元和/或神经胶质细胞中。其次，在目标1-2的延伸中，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 3信号传导元件是否与异常性疼痛共变。在神经损伤或持续性炎症后的不同时间，我们将评估：行为和A）PPAR 3 mRNA和蛋白质; B）磷酸化的PPAR 3;和C）LC/MS/MS的15 d-PGJ 2水平。公共卫生相关性慢性疼痛管理是一个主要的科学和卫生保健挑战，因为目前的镇痛药物很少在没有严重副作用的情况下提供足够的疗效。我们建议，过氧化物酶体增殖物激活受体γ（PPAR 3），如罗格列酮和吡格列酮，代表一类新的镇痛/抗异常性疼痛的化合物的配体。这些概念上的创新实验是重要和及时的，因为TZD可用于糖尿病，并在CNS神经退行性疾病的临床试验中。因此，我们假设的证实可能会导致慢性疼痛的临床治疗的快速转化。