Mechanisms and Therapeutic Strategies for Post-traumatic Headache

创伤后头痛(PTH)通常发生在轻度创伤性脑损伤(MTBI)之后，也称为 脑震荡。甲状旁腺激素是一种继发性头痛，通常表现为偏头痛样表型，并被细分为 急性或持续性(PPTH)取决于受伤后3个月内是否痊愈。病理生理学 甲状旁腺激素和甲状旁腺激素的关系尚不清楚，也没有针对这些疾病的循证治疗方法。关键是， 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。部分患者出现PPTH的原因尚不清楚，但可能与风险有关 这些因素包括既有偏头痛和既往小脑损伤的经历。我们已经开发出一种方法 探讨甲状旁腺激素和甲状旁腺激素的发病机制及可能的治疗策略。使用权重 总结mTBI生物力学特性和临床特征的雄性和雌性小鼠Drop方法， 我们已经证明，单次mTBI足以引起临床上相关的PTH症状，包括急性 痛觉过敏期、降钙素基因相关肽水平升高和诱发皮质扩散阈值降低 抑郁症(CSD)。此外，我们还探讨了从急性疼痛到慢性疼痛的过渡 国家可能依赖“疼痛记忆”，这可以用痛觉过敏启动的“两次击打”模型来研究，其中 之前的侮辱会让人更容易受到随后的挑衅性刺激。因此，在解决急性 异常痛觉，mTBI小鼠进入持续时间较长的持续阶段(PPTH)，在此阶段，异常痛觉可 由生理上相关的和常见的偏头痛触发因素恢复，包括压力。CGRP成立于 偏头痛的发病机制和我们的数据也表明了在促进甲状旁腺激素方面的重要作用。使用一种或一种 CGRP抗体或与肉毒杆菌毒素A(Botox)联用可预防mTBI相关的痛觉异常(PTH)以及 随后出现以PPTH为代表的异位痛觉。然而，mTBI致敏后CGRP的阻断 阿司匹林在阻断引起的痛觉过敏方面无效，而肉毒杆菌毒素仍然保持疗效。我们有 假设mTBI导致脑膜传入释放CGRP促进甲状旁腺素和中枢神经 PPTH发生的基础致敏作用，但PPTH可能维持在CGRP非依赖状态 时尚。此外，我们假设，在mTBI事件之前现有的敏感化将促进脆弱性 对降钙素基因相关肽非依赖性PPTH的发展有重要意义。我们通过两个相关的假设来探讨这些假设， 独立，旨在使用行为、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与mTBI相关的结果 PTH的表达，以及这些治疗是否能阻止PPTH的表达。目标2将确定先前的敏化 促进更严重、持久和抗降钙素基因相关肽的PPTH。我们的研究将填补重大的知识空白 关于CGRP在促进甲状旁腺激素中的作用以及预先存在的敏化在建立CGRP- 独立PPTH。这些信息将影响治疗，并指导新疗法的发现。

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.