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建议：急性到智商口面痛的模型和机制摘要/摘要该申请应解决广泛的挑战领域（15）转化科学和特定挑战主题15- de-102*：新模型和措施的新模型和措施。预测从急性到慢性疼痛的过渡的关键特征仍未解决。本提案探讨了小胶质细胞“启动”是否在解释从急性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了各种增强的疼痛状态。在疼痛背景下尚未探索的神经胶质功能的一个重要方面是敏感或“启动”的小胶质细胞反应的效果。疼痛领域以外的研究表明，小胶质激活的过去历史可以极大地改变他们对新挑战的反应。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的状态，这是已知的急性转变为三叉神经系统中慢性疼痛的合并症。虽然在如此底漆的状态下，小胶质细胞现在非常重视新的挑战，比以前更强大，更长。我们认为，这种先前的小胶质启动可以为暂时性关节（TMJ）疾病和其他口面疼痛疾病的慢性疼痛转变为慢性疼痛奠定基础。引发脊柱小胶质细胞的重新激活可能会导致从急性疼痛到慢性疼痛的过渡，这在大小和持续时间中都大大扩增。 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).一旦定义和精制了强大的模型，将对潜在的神经胶质细胞对从急性到慢性疼痛的过渡进行初始探索。根据时间的限制，这仅仅是基于该项目生成的数据，在将来的提案中进行彻底调查的第一步。在这里，将使用FDA批准的两个血脑屏障抑制剂进行研究确定最健壮的模型，用于治疗神经性疼痛：Ibudilast（AV411）和倾向叶line（SLC022）。这些非阿片类药物，非添加性药物将在初始筛选中进行测试，以确定两种化合物是否能够防止急性向慢性疼痛过渡。如预期的那样，如果他们这样做，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得慢性的基础科学理解中提供重大进步，并提供可预防和扭转慢性过渡的临床测试手段。探索已知的合并症是如何通过诱导小胶质细胞进入过度反应性的启动状态的从急性到慢性疼痛的过渡奠定了基础，这是一个从未探索过的主题，并且在其潜在的实用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，以研究从急性到慢性口面痛的过渡，基于以下前提，即第一个挑战（“命中1”：先前的疼痛，压力，创伤/炎症，阿片类药物）将显着增强对随后对Trigeminal System（Trigeminal Systems）的挑战（命中2命中）的痛苦。我们认为，这种向慢性疼痛的过渡将是由于命中1对神经胶质的敏化，从而导致它们大规模响应对HIT 2的响应，并且使用临床上相关的神经胶质激活抑制剂的治疗将阻止过渡到慢性疼痛。