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

描述（由申请人提供）：NIDCR提案：急性向慢性口面疼痛转变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。预测从急性疼痛到慢性疼痛转变的关键特征仍然没有得到解决。本提案探讨是否小胶质细胞的“启动”可能是特别重要的，在解释从急性到慢性疼痛的进展。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探索，这是一个敏化的，或“引发”，小胶质细胞反应的影响。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，这些药物是三叉神经系统中急性疼痛向慢性疼痛过渡的已知共病。在这样一个启动状态下，小胶质细胞现在对新的挑战做出了戏剧性的过度反应，比以前更强大，更长。我们相信，这种先前的小胶质细胞启动可以为颞下颌关节（TMJ）疾病和其他口面疼痛疾病的急性疼痛向慢性疼痛的过渡奠定基础。引发的脊髓小胶质细胞的重新激活可能导致从急性疼痛到慢性疼痛的转变，这是神经炎症反应的结果，其在幅度和持续时间上都大大放大。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疼痛的转变，其前提是第一次挑战（先前的疼痛，压力，创伤/炎症，阿片类药物）将显著增强随后对三叉神经系统的挑战（由TMJ或硬脑膜炎症引起的面部异常性疼痛）引起的疼痛。一旦定义和完善了强大的模型，将对神经胶质细胞对急性疼痛向慢性疼痛过渡的潜在影响进行初步探索。由于时间的限制，这仅仅是根据本项目产生的数据在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，用于使用FDA现在批准用于旨在治疗神经性疼痛的临床试验的两种血脑屏障渗透性胶质细胞活化抑制剂进行研究：异丁司特（AV 411）和丙戊茶碱（SLC 022）。这些非阿片类、非成瘾性药物将在初始筛选中进行测试，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。如果他们这样做，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在我们对急性疼痛如何变成慢性疼痛的基础科学理解方面取得重大进展，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到慢性疼痛的转变奠定基础，这是一个从未探索过的话题，在其潜在的实践和理论应用中令人兴奋。 公共卫生相关性：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疼痛的转变，其前提是第一次挑战（“Hit 1”：先前的疼痛、压力、创伤/炎症、阿片类药物）将显著增强由随后对三叉神经系统的挑战（“Hit 2”：TMJ或硬脑膜的炎症）诱导的疼痛。我们认为，这种向慢性疼痛的转变将是由于Hit 1对胶质细胞的致敏作用，导致它们对Hit 2的反应过度，并且用临床相关的胶质细胞活化抑制剂治疗将防止向慢性疼痛的转变。

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.