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: 7805658
• 负责人: LINDA WATKINS
• 金额: $ 34.09万
• 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 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7805658
• 关键词: Acute; Acute Pain; Address; Animal Model; Area; Astrocytes; Basic Science; Blood - brain barrier anatomy; Chronic; Clinical Trials; Data; Development; Dura Mater; Epidemic; Evolution; Exposure to; FDA approved; Face; Future; Inflammation; Investigation; Laparotomy; Lead; Maintenance; Measures; Mediating; Microglia; Modeling; Morbidity - disease rate; 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：急性向慢性口面部疼痛转变的模型和机制 项目摘要/摘要 本申请解决了广泛的挑战领域 (15) 转化科学和具体挑战主题 15-DE-102*：临床前慢性疼痛研究的新模型和措施。预测急性疼痛向慢性疼痛转变的关键特征仍未解决。本提案探讨小胶质细胞“启动”在解释从急性疼痛到慢性疼痛的进展中是否特别重要。小胶质细胞和星形胶质细胞的激活介导不同的增强疼痛状态。神经胶质功能的一个重要方面尚未在疼痛的背景下进行探索，即敏化或“启动”小胶质细胞反应的影响。疼痛领域之外的研究表明，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、创伤和炎症以及接触阿片类药物达到启动状态，这些是三叉神经系统急性向慢性疼痛转变的已知共病。在这样的准备状态下，小胶质细胞现在对新挑战的反应显着过度，比以前更强、更持久。我们相信这种预先的小胶质细胞启动可以为颞下颌关节（TMJ）疾病和其他口面部疼痛疾病的急性疼痛转变为慢性疼痛奠定基础。由于神经炎症反应的强度和持续时间都大大增强，激活的脊髓小胶质细胞的重新激活可能导致从急性疼痛转变为慢性疼痛。该提案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，前提是第一次挑战（先前的疼痛、压力、创伤/炎症、阿片类药物）将显着增强随后对三叉神经系统的挑战（由颞下颌关节或硬脑膜炎症引起的面部异常性疼痛）引起的疼痛。一旦定义和完善了稳健的模型，将初步探索神经胶质细胞对急性疼痛向慢性疼痛转变的潜在影响。由于时间限制，这只是在基于该项目生成的数据的未来提案中进行彻底调查的第一步。在这里，将确定最稳健的模型进行研究，使用目前 FDA 批准用于治疗神经性疼痛的临床试验的两种血脑屏障渗透性神经胶质激活抑制剂：异丁司特 (AV411) 和丙戊茶碱 (SLC022)。这些非阿片类、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预防急性疼痛向慢性疼痛的转变。如果它们确实如预期的那样，这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的基础科学理解提供重大进展，并提供一种可临床测试的方法来预防和逆转向慢性的转变。探索已知的共病如何通过诱导小胶质细胞进入过度反应的启动状态来为从急性疼痛过渡到慢性疼痛奠定基础，这是一个以前从未探索过的话题，其潜在的实际和理论应用令人兴奋。 公共健康相关性：本提案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，前提是第一次挑战（“打击1”：先前的疼痛、压力、创伤/炎症、阿片类药物）将显着增强随后对三叉神经系统的挑战（“打击2”：颞下颌关节或硬脑膜的炎症）引起的疼痛。我们认为，这种向慢性疼痛的转变是由于神经胶质细胞对 Hit 1 的敏感性，导致它们对 Hit 2 做出过度反应，并且使用临床相关的神经胶质激活抑制剂进行治疗将防止向慢性疼痛的转变。