Models and mechanisms for the transition of acute-to-chronic orofacial pain

急性至慢性口面部疼痛转变的模型和机制

• 批准号: 7936108
• 负责人: LINDA WATKINS
• 金额: $ 33.79万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-22 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7936108
• 关键词: Acute; Acute Pain; Address; Animal Model; Area; Astrocytes; Basic Science; Blood - brain barrier anatomy; Chronic; Clinical Trials; Comorbidity; Data; Development; Dura Mater; Epidemic; Evolution; Exposure to; FDA approved; Face; Future; Inflammation; Investigation; Laparotomy; Lead; Maintenance; Measures; Mediating; Microglia; Modeling; National Institute of Dental and Craniofacial Research; Neuroglia; Opioid; Orofacial Pain; Pain; Pain Disorder; Pain Research; Pharmaceutical Preparations; Rattus; Recording of previous events; Research; Spinal; Staging; Stress; Study models; Temporomandibular Joint; Temporomandibular Joint Disorders; Testing; Time; Translational Research; Trauma; Trigeminal Neuralgia; Trigeminal System; abstracting; allodynia; base; chronic pain; clinically relevant; inhibitor/antagonist; painful neuropathy; pre-clinical; prevent; propentofylline; public health relevance; response

DESCRIPTION (provided by applicant): NIDCR Proposal: Models and mechanisms for the transition of acute-to-chronic orofacial pain Project Summary/Abstract This application addresses broad Challenge Area (15) Translational Science & specific Challenge Topic 15- DE-102*: New Models and Measures in Pre-Clinical Chronic Pain Research. The critical features that predict the transition from acute to chronic pain remain unresolved. The present proposal explores whether microglial "priming" may be of particular importance in explaining the progression from acute to chronic pain. Activation of microglia & astrocytes mediates diverse enhanced pain states. One important aspect of glial functioning that has not been explored in the context of pain is the effect of a sensitized, or "primed", microglial response. Research outside of the field of pain indicates that the past history of microglial activation can greatly alter their response to new challenges. Microglia can reach a primed state via prior stress, pain, trauma & inflammation, & exposure to opioids, which strikingly are known co-morbidities for the transition of acute to chronic pain in the trigeminal system. While in such a primed state, microglia now dramatically over-respond to new challenges, stronger & longer than before. We believe such prior microglial priming can set the stage for the transition of acute to chronic pain in temporomandibular joint (TMJ) disorders & other orofacial pain disorders. Re-activation of primed spinal microglia may lead to a transition from acute pain to chronic pain as a result of a neuroinflammatory response that is greatly amplified in both magnitude & duration. This proposal aims to develop new rat models for the study of the transition from acute to chronic orofacial pain, based on the premise that a first challenge (prior pain, stress, trauma/inflammation, opioids) will markedly enhance pain induced by a subsequent challenge to the trigeminal system (facial allodynia induced by inflammation of either the TMJ or dura). Once robust models are defined & refined, an initial exploration of potential glial cell influence on the transition from acute to chronic pain will be undertaken. This is, by necessity of time constraints, meant as simply the first step toward a thorough investigation to be undertaken in a future proposal based on the data generated by this project. Here, the most robust models will be determined for study using the two blood brain barrier permeable glial activation inhibitors now approved by the FDA for clinical trials aimed at treating neuropathic pain: ibudilast (AV411) & propentofylline (SLC022). These non-opioid, non-addictive drugs will be tested in an initial screen to determine whether either or both compounds may be able to prevent the transition of acute to chronic pain. If they do, as expected, this would suggest that preventing or suppressing glial priming may provide a significant advance in our basic science understanding of how acute pain becomes chronic, as well as provide a clinically testable means by which to prevent & reverse the transition to chronicity. Exploring how known co-morbidities set the stage for the transition from acute to chronic pain by inducing microglia to enter into an over-reactive primed state is a topic never before explored & exciting in its potential practical & theoretical applications. PUBLIC HEALTH RELEVANCE: This proposal aims to develop new rat models for the study of the transition from acute to chronic orofacial pain, based on the premise that a first challenge ("Hit 1": prior pain, stress, trauma/inflammation, opioids) will markedly enhance pain induced by a subsequent challenge to the trigeminal system ("Hit 2": inflammation of either the TMJ or dura). We believe that this transition to chronic pain will be due to sensitization of glia by Hit 1, causing them to massively over respond in response to Hit 2, and that treatment with clinically-relevant glial activation inhibitors will prevent the transition to chronic pain.

描述（由申请人提供）：NIDCR提案：急性到慢性口腔面部疼痛过渡的模型和机制项目摘要/摘要本申请涉及广泛的挑战领域（15）转化科学和特定挑战主题15- DE-102*：临床前慢性疼痛研究的新模型和措施。预测从急性到慢性疼痛过渡的关键特征仍未解决。目前的建议探讨是否小胶质细胞“启动”可能在解释从急性到慢性疼痛的进展中特别重要。小胶质细胞和星形胶质细胞的激活介导了多种增强的疼痛状态。神经胶质功能的一个重要方面尚未在疼痛的背景下探索是致敏的，或“启动”，小胶质反应的影响。疼痛领域以外的研究表明，小胶质细胞激活的过去历史可以极大地改变它们对新挑战的反应。小胶质细胞可以通过先前的压力、疼痛、创伤和炎症以及暴露于阿片类药物而达到启动状态，这些都是三叉神经系统急性到慢性疼痛转变的显著合并症。在这种启动状态下，小胶质细胞现在对新的挑战反应过度，比以前更强、更持久。我们相信这种预先的小胶质启动可以为颞下颌关节（TMJ）疾病和其他口腔面部疼痛疾病的急性到慢性疼痛转变奠定基础。脊髓小胶质细胞的再激活可能导致急性疼痛向慢性疼痛的转变，这是神经炎症反应的结果，在强度和持续时间上都被大大放大。基于第一次刺激（先前的疼痛、应激、创伤/炎症、阿片类药物）将显著增强三叉神经系统随后刺激（由颞下颌关节或硬脑膜炎症引起的面部异常痛）引起的疼痛，本研究旨在开发新的大鼠模型，用于研究从急性到慢性口面部疼痛的转变。一旦健全的模型被定义和完善，神经胶质细胞对从急性到慢性疼痛转变的潜在影响的初步探索将进行。由于时间的限制，这仅仅是为了在今后的提案中根据本项目产生的数据进行彻底调查而迈出的第一步。目前，FDA已批准用于治疗神经性疼痛的两种血脑屏障渗透性胶质细胞激活抑制剂：布替拉斯特（AV411）和丙烯茶碱（SLC022）。这些非阿片类药物、非成瘾性药物将在初步筛选中进行测试，以确定其中一种或两种化合物是否能够防止急性到慢性疼痛的转变。如果他们确实如此，正如预期的那样，这将表明预防或抑制神经胶质启动可能会为我们对急性疼痛如何变成慢性疼痛的基础科学理解提供重大进展，并提供一种临床可测试的方法来预防和逆转向慢性疼痛的转变。探索已知的合并症如何通过诱导小胶质细胞进入过度反应的启动状态，为从急性到慢性疼痛的过渡奠定基础，这是一个从未被探索过的话题，在其潜在的实践和理论应用中令人兴奋。