Mechanisms and Therapeutic Strategies for Post-traumatic Headache

创伤后头痛的机制和治疗策略

• 批准号: 10217274
• 负责人: Trent Anderson
• 金额: $ 48.73万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-15 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10217274
• 关键词: Acceleration; Acute; Address; Animals; Behavioral; Biomechanics; Blood; Botox; Brain Concussion; Calcitonin Gene-Related Peptide; Cells; Cephalic; Clinical; Common Migraine; Conscious; Data; Development; Drops; Electrophysiology (science); Equilibrium; Event; Evidence based treatment; Female; Functional disorder; Goals; Headache; Impairment; Individual; Injury; Knowledge; Laboratories; Lead; Memory; Meningeal; Methods; Migraine; Modeling; Monoclonal Antibodies; Motor; Mus; Neurons; Nociceptive Stimulus; Nociceptors; Outcome; Pain; Pathogenesis; Patient-Focused Outcomes; Patients; Peptide antibodies; Peripheral; Pharmaceutical Preparations; Phase; Phenotype; Physiological; Post-Traumatic Headaches; Property; Recording of previous events; Residual state; Resistance; Resolution; Risk Factors; Role; Rotation; Running; Severities; Skull Fractures; Spreading Cortical Depression; Stimulus; Stress; Symptoms; TBI treatment; Therapeutic; Traumatic Brain Injury; Trigeminal Nuclei; Unconscious State; Weight; allodynia; alpha Toxin; base; central sensitization; chronic pain; clinically relevant; cranium; experience; guided inquiry; improved; male; mild traumatic brain injury; neurochemistry; neuropathology; non-opioid analgesic; novel; novel therapeutics; prevent; treatment strategy

Post-traumatic headache (PTH) commonly occurs following mild traumatic brain injury (mTBI), also known as concussion. PTH is a secondary headache that often presents with a migraine-like phenotype and is subdivided as acute or persistent (PPTH) depending on whether it resolves within 3 months after injury. The pathophysiology of PTH and PPTH is not understood and no evidence-based treatments exist for these conditions. Critically, PPTH might differ from PTH, not only in the duration but also in underlying mechanisms and responsiveness to treatment. The reasons for emergence of PPTH in some patients remain unclear but may be related to risk factors including pre-existing migraine and the experience of a previous mTBI. We have developed an approach to investigate the mechanisms of PTH and PPTH as well as potential strategies for treatment. Using a weight drop method in male and female mice that recapitulates biomechanical properties and clinical features of mTBI, we have shown that a single mTBI is sufficient to induce clinically relevant PTH symptoms including an acute period of allodynia, elevated CGRP blood levels and lowered thresholds for induction of cortical spreading depression (CSD). Additionally, we have explored the concept that the transition from acute to chronic pain states may rely on a “pain memory” that can be studied using the “two-hit” model of hyperalgesic priming where a prior insult confers vulnerability to a subsequent provocative stimulus. Thus, following resolution of acute allodynia, mTBI mice transition into a long-lasting persistent phase (PPTH) where, remarkably, allodynia can be reinstated by physiologically relevant and common migraine triggers, including stress. CGRP is established in migraine pathogenesis and our data also suggest an important role in promoting PTH. Treatment with either a CGRP antibody or with onabotulinum toxin A (botox) prevents mTBI-related allodynia (PTH) as well as subsequent provoked allodynia representative of PPTH. However, blockade of CGRP after mTBI sensitization is established is ineffective in blocking provoked allodynia, while botox still maintains efficacy. We have hypothesized that mTBI results in CGRP release from meningeal afferents promoting PTH and central sensitization that underlies the development of PPTH, but that PPTH may be maintained in a CGRP-independent fashion. Additionally, we hypothesize that existing sensitization prior to a mTBI event will promote vulnerability to the development of CGRP-independent PPTH. We explore these hypotheses with two related but, independent, aims using behavioral, neurochemical, immunohistochemical and electrophysiolgical analyses. Aim 1 will determine whether, and when currently available therapies can block mTBI-related outcomes relevant to PTH and if these treatments can prevent the expression of PPTH. Aim 2 will determine if prior sensitization promotes more severe, long-lasting and CGRP-resistant PPTH. Our studies will fill in significant knowledge gaps about the role of CGRP in promoting PTH and the importance of pre-existing sensitization in establishing CGRP- independent PPTH. Such information will influence treatment as well as guide the discovery of new therapies.

创伤后头痛（PTH）通常发生在轻度创伤性脑损伤（mTBI）后，也称为 脑震荡PTH是一种继发性头痛，常表现为偏头痛样表型， 急性或持续性（PPTH）取决于它是否在受伤后3个月内解决。病理生理学 PTH和PPTH之间的关系尚不清楚，这些疾病也没有循证治疗。重要的是， PPTH可能与PTH不同，不仅在持续时间上，而且在潜在机制和对 治疗一些患者出现PPTH的原因尚不清楚，但可能与风险有关。 因素包括预先存在的偏头痛和以前的mTBI的经验。我们开发了一种方法 探讨甲状旁腺激素（PTH）和甲状旁腺激素（PPTH）的发病机制及可能的治疗策略。使用权重 在雄性和雌性小鼠中的滴法，其概括了mTBI的生物力学特性和临床特征， 我们已经表明，单次mTBI足以诱导临床相关的PTH症状，包括急性 异常性疼痛期，CGRP血液水平升高，皮层扩散诱导阈值降低 抑郁症（CSD）。此外，我们还探讨了从急性疼痛到慢性疼痛的转变 状态可能依赖于“疼痛记忆”，该“疼痛记忆”可以使用痛觉过敏启动的“两次打击”模型来研究， 先前的侮辱使人容易受到随后的刺激。因此，在解决急性 在异常性疼痛中，mTBI小鼠过渡到持久持续期（PPTH），其中，显著地，异常性疼痛可以被抑制。 由生理相关的和常见的偏头痛触发恢复，包括压力。CGRP建立于 偏头痛的发病机制和我们的数据也表明在促进PTH的重要作用。治疗与一个 CGRP抗体或肉毒杆菌毒素A（botox）可预防mTBI相关的异常性疼痛（PTH）， 随后引起的异常性疼痛代表PPTH。然而，mTBI致敏后阻断CGRP 在阻断诱发的异常性疼痛方面是无效的，而肉毒杆菌毒素仍然保持有效性。我们有 假设mTBI导致CGRP从脑膜传入神经释放，促进PTH和中枢 致敏是PPTH发展的基础，但PPTH可能以CGRP非依赖性方式维持。 时尚.此外，我们假设，在mTBI事件发生之前，现有的致敏作用将促进脆弱性 不依赖CGRP的PPTH的发展。我们用两个相关的假设来探讨这些假设， 独立，目的是使用行为，神经化学，免疫组织化学和电生理分析。 目标1将确定目前可用的治疗方法是否以及何时可以阻断mTBI相关的结局 以及这些治疗是否可以阻止PPTH的表达。目标2将确定既往致敏是否 促进更严重，持久和CGRP耐药的PPTH。我们的研究将填补重大的知识空白 关于CGRP在促进PTH中的作用以及预先存在的致敏在建立CGRP中的重要性， 独立PPTH。这些信息将影响治疗，并指导新疗法的发现。