A nonpharmacological therapeutic intervention of TBI-induced facial allodynia/hyperalgesias in a rodent model

缺乏对基础神经生物学的了解，而神经生物学是发展和坚持的基础 创伤后脑损伤(TBI)引起的急性和慢性疼痛的原因目前尚不清楚，这进一步限制了我们的能力 以开发适当的治疗方法。电针(EA)是一种已经使用多年的康复方式。 然而，它的作用模式在很大程度上是未知的，尽管越来越多的证据表明，大脑和脊髓 脊髓主要参与针灸刺激的处理。针灸的止痛作用是 有据可查。此外，针灸在急性和慢性疾病中调节全身炎症的强大能力 慢性事件最近在多种疾病情况下被记录在案。然而，这还不够 使用该程序启动脑损伤临床试验的临床前数据。这项提案的主要目标是测试 电针缓解疼痛/头痛的量效关系及作用机制 闭合性头部创伤性脑损伤(CH-TBI)的临床相关啮齿动物模型的行为。这一模式非常接近 类似于钝性头部创伤，在涉及汽车头部碰撞的人类受伤情况下可见 车祸、运动和战场上受到的冲击伤。该CH-TBI啮齿动物模型展出 进行性和持续性口面部和躯体疼痛/头痛样症状的全面证据 由非痛苦的刺激引起的。这些疼痛/头痛样症状与几个 已知的疼痛信号受体和分子沿着三叉神经和脊髓丘脑神经元疼痛通路。 由于颅脑损伤后引起慢性疼痛和头痛是军人和文职人员的主要健康问题， 旨在探索潜在神经生物学和靶向治疗的临床前研究是至关重要的。因此， 这项建议中的两个机制驱动的具体目标的目的是增进我们对 电针治疗的神经生物学影响颅脑损伤后面部疼痛/头痛样行为的变化 和躯体痛觉过敏/超感痛觉。我们最近在成人中使用温和的CH撞击加速TBI模型进行的研究 SpragueDawley大鼠表现出显著和持久的三叉神经和足底痛觉过敏 艺术操作型口腔和爪痛奖赏/冲突测试范式。特定目标1将评估治疗方法 电针治疗对颅脑损伤所致口面部和爪部急性痛敏/痛敏的影响 (创伤性脑损伤后立即)和慢性(2个月)时间点，使用2种不同的持续时间(2周对4周) 周)进行电针治疗。具体目标2将解决创伤性脑损伤和治疗引起的疼痛机制变化 三叉神经和躯体疼痛通路中的信号传递；这些研究将量化全面的 一系列基于MRI的与疼痛信号和炎症相关的生物标志物、分子和受体 基于定量MRI和免疫组织化学(IHC)的三叉神经痛和躯体痛通路 技巧。研究人员提出，电针治疗将安全、显著地减少口腔面部 和躯体痛觉过敏；因此，这种疗法具有快速临床转化的潜力。 作为治疗颅脑损伤引起的疼痛和头痛的重要非药物疗法。调查人员进一步提出， 电针治疗引起的口面部和躯体疼痛敏感性的显著降低将伴随着 面部和面部炎症生物标志物和疼痛信号分子/受体显著减少 躯体痛觉通路。MRI和IHC数据将进一步确定作用机制的细节。这些研究 有可能增加我们对脑外伤引起的疼痛/头痛的神经生物学和 电针的受益机制、开始治疗的适当时间、治疗持续时间，以及进一步 为脑外伤引起的男女疼痛/头痛治疗的发展提供一个平台。我们有 假设电针的有效性将是最大的，如果它是在损伤后，显着之前的急性给药 痛觉通路中会出现不适应的可塑性。此外，4周的治疗效果将显著改善。 结果与两周的治疗相比，这是由于疼痛通路中基于刺激的持久引导可塑性。

The lack of understanding of the fundamental neurobiology that underlies the development and persistence of post-traumatic brain injury (TBI)-induced acute and chronic pain is currently unknown, further limiting our ability to develop appropriate treatments. Electro-acupuncture (EA) is a healing modality that has been in use for years. It's modes of action, however, are largely unknown, although there is increasing evidence that brain and spinal cord are primarily involved in the processing of acupuncture stimuli. The analgesic effects of acupuncture are well documented. In addition, acupuncture's powerful ability to modulate systemic inflammation during acute and chronic events has recently been documented in multiple disease conditions. However, there is not enough preclinical data using the procedure to initiate a clinical trial for TBI. The main objective of this proposal is to test the dose-dependent effectiveness and mechanism of action of EA treatment to alleviate pain/headache-like behavior in a clinically relevant rodent model of closed head traumatic brain injury (CH-TBI). This model closely resembles blunt trauma head injury seen in human injury situations involving head impact from automobile crashes, sports, and from blast injury received in battlefield situations. This CH-TBI rodent model exhibited comprehensive evidence of progressive and enduring orofacial and somatic pain/headache-like symptoms induced by non-painful stimulation. These pain/headache-like symptoms correlated with changes in several known pain signaling receptors and molecules along the trigeminal and spinothalamic neuronal pain pathways. Since post-TBI induced chronic pain and headache are major health issue in both military and civilian personnel, preclinical research aiming at the exploration of underlying neurobiology, and targeted therapy is vital. Therefore, the objective of two mechanism driven Specific Aims in this proposal is to enhance our understanding of the neurobiology of EA therapy-influenced changes in TBI-induced pain/headache-like behaviors tested as facial and somatic hyperalgesia/allodynia. Our recent studies using a mild CH impact acceleration TBI model in adult Sprague Dawley rats revealed significant and enduring trigeminal and plantar hyperalgesia using a state of the art operant orofacial and paw pain reward/conflict testing paradigm. Specific Aim 1 will evaluate the therapeutic potential of EA therapy on the progression of TBI-induced orofacial and paw allodynia/hyperalgesias at acute (immediate after TBI) and chronic (2 months) time points after TBI using 2 different durations (2-week vs. 4- week) of EA therapy. Specific Aim 2 will address TBI and therapy-induced changes in mechanisms of pain signaling in trigeminal and somatic pain pathways; these studies will quantitate of changes in a comprehensive array of MRI-based biomarkers, molecules, and receptors related to pain signaling and inflammation in the trigeminal and somatic pain pathways using quantitative MRI, and immunohistochemistry (IHC) based techniques. The investigators propose that EA treatment will produce a safe, significant reduction of orofacial and somatic allodynia/hypersensitivities; accordingly, this therapy has the potential for rapid clinical translation as significant drug free therapy to treat TBI-induced pain and headache. Investigators further propose that the EA treatment-induced significant reduction in orofacial and somatic pain sensitivity will be accompanied by significant reduction of inflammatory biomarkers, and pain signaling molecules/receptors in the facial and somatic pain pathways. MRI and IHC data will further identify details of the mechanisms of action. These studies have the potential to increase our understanding of the neurobiology of TBI-induced pain/headache and the mechanisms of benefits from EA, appropriate time of treatment initiation, duration of treatment, and further provide a platform for the development of TBI-induced pain/headache treatment in both genders. We do hypothesize that the effectiveness of EA will be maximal if it is administered acutely after injury before significant maladaptive plasticity in pain pathways happen. Moreover, 4 weeks treatment will produce significantly better outcomes compared to 2-week treatment due to stimuli-based enduring guided plasticity in the pain pathways.