PPAR Inhibition of Spinal Pain Transmission

PPAR 抑制脊髓疼痛传播

• 批准号: 7796408
• 负责人: BRADLEY K. TAYLOR
• 金额: $ 32.36万
• 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/7796408
• 关键词: Adverse effects; Agonist; Analgesics; Antidiabetic Drugs; Astrocytes; Basic Science; Behavior; Behavioral; Chronic; Clinical Treatment; Clinical Trials; Cobalt; DNA Binding; Diabetes Mellitus; Dorsal; Dose; Electrophoretic Mobility Shift Assay; FDA approved; Genetic; Glial Fibrillary Acidic Protein; 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; Nociception; Oral Administration; PPAR gamma; Pain; Pain management; Peripheral; Peripheral nerve injury; Peroxisome Proliferator-Activated Receptors; Pioglitazone; Protein Isoforms; Proteins; Rattus; Receptor Inhibition; Receptor Signaling; Research; Signal Transduction; Spinal; Spinal Cord; Spinal cord posterior horn; Stimulus; System; Testing; Therapeutic; Time; Tissues; Translations; Western Blotting; allodynia; chronic pain; dorsal horn; inflammatory neuropathic pain; injured; innovation; mutant; nerve injury; neurotransmission; 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（由申请人提供）：过氧化物酶体增殖物激活的受体伽马（PPAR 3）被充分表征，作为抗糖尿病药物（TZD）类的关键目标。我们的初步结果描述了背角中PPAR 3 mRNA和蛋白质的存在。此外，我们证明，通过鞘内给予罗格列酮（A TZD）和15d-PGJ2（一种内源性PPAR 3配体），在剂量和PPAR 3依赖性的方式中，与炎症或神经损伤相关的机械和热超敏反应迅速降低。并通过系统地给药，pioglitazone，bbb-permeant，FDA批准的配体。该提议的中心假设是，背角中PPAR3的配体依赖性激活减少了损伤诱导的脊髓神经元和神经胶质的激活，从而抑制了炎症性和神经性疼痛的行为迹象。本应用的目的是确定抑制炎症或神经性疼痛的抑制作用的机制，重点是吡格列酮。我们的研究计划的长期目标是利用PPAR信号传导的治疗潜力减轻人类的慢性疼痛。 AIM 1将检验PPAR 3激动剂减少异肌和痛觉过敏的假设。我们将使用药理学剂和神经系统特异性PPAR 3缺失突变体来确定脊髓中PPAR 3信号传导对慢性疼痛的诱导和维持的贡献。首先，我们将确定吡格列酮和15d-PGJ2的单一鞘内或全身给药会减少炎症和神经性疼痛的行为迹象。我们预测他们的镇痛作用将被PPAR 3拮抗剂阻塞。其次，我们将确定慢性鞘内或口服PPAR 3激动剂是在组织或神经损伤之前或之后开始的，这会减少炎症和神经性疼痛的行为迹象。第三，我们预测，在神经元特异性PPAR 3敲低的小鼠中不会发生抗差异动作。 AIM 2将检验以下假设：PPAR 3配体会减少背角中神经元和小胶质细胞的损伤诱导的激活。损伤大鼠的体感觉刺激诱导了背角的表面层层中立即的早期基因C-FOS的表达。我们预测，鞘内吡格列酮将减少FOS免疫反应性神经元的炎症和神经损伤诱导的表达，以及OX-42的表达，Ox-42（小胶质细胞激活的标志物）。 AIM 3将检验以下假设：内源性PPAR 3系统在调节性抑制异常性尼亚。首先，我们将确定在疼痛期间激活的神经元和/或神经胶质中是否发生PPAR3表达。其次，在AIMS 1-2的扩展中，我们将确定受体拮抗剂和遗传缺失是否会增加异肌和神经/神经胶质激活。如果是肯定的，那么我们将确定PPAR3信号元件是否与异常性症相反。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 3 mRNA和蛋白质； b）磷酸化的PPAR 3; c）具有LC/MS/MS的15d-PGJ2水平。公共卫生相关性慢性疼痛管理是一项主要的科学和医疗保健挑战，因为当前的镇痛药在没有严重副作用的情况下很少提供足够的功效。我们提出，过氧化物酶体增殖物激活的受体伽马（PPAR 3）（例如罗格列酮和吡格列酮）代表了一类新型的镇痛 /抗合金化合物。这些在概念上创新的实验很重要，并且及时，因为TZD可用于糖尿病，并且正在接受中枢神经系统神经退行性疾病的临床试验。因此，确认我们的假设可能会导致快速转化为慢性疼痛的临床治疗。