Introduction

Posttraumatic headache is one of the most common, debilitating, and difficult symptoms to manage after a traumatic head injury. The development of novel therapeutic approaches is nevertheless hampered by the paucity of preclinical models and poor understanding of the mechanisms underlying posttraumatic headache. To address these shortcomings, we previously characterized the development of posttraumatic headache-like pain behaviors in rats subjected to a single mild closed head injury using a 250 g weight drop. Here, we conducted a follow-up study to further extend the preclinical research toolbox for studying posttraumatic headache by exploring the development of headache-like pain behaviors in male rats subjected to a single, but more severe head trauma (450 g) as well as following repetitive, subconcussive head impacts (150 g). In addition, we tested whether these behaviors involve peripheral calcitonin gene-related peptide signaling by testing the effect of systemic treatment with an anti-calcitonin gene-related peptide monoclonal antibody (anti-calcitonin gene-related peptide mAb).

Methods

Adult male Sprague Dawley rats (total n = 138) were subjected to diffuse closed head injury using a weight-drop device, or a sham procedure. Three injury paradigms were employed: A single hit, using 450 g or 150 g weight drop, and three successive 150 g weight drop events conducted 72 hours apart. Changes in open field activity and development of cephalic and extracephalic tactile pain hypersensitivity were assessed up to 42 days post head trauma. Systemic administration of the anti-calcitonin gene-related peptide mAb or its control IgG (30 mg/kg) began immediately after the 450 g injury or the third 150 g weight drop with additional doses given every 6 days subsequently.

Results

Rats subjected to 450 g closed head injury displayed an acute decrease in rearing and increased thigmotaxis, together with cephalic tactile pain hypersensitivity that resolved by 6 weeks post-injury. Injured animals also displayed delayed and prolonged extracephalic tactile pain hypersensitivity that remained present at 6 weeks post-injury. Repetitive subconcussive head impacts using the 150 g weight drop, but not a single event, led to decreased vertical rearing as well as cephalic and extracephalic tactile pain hypersensitivity that resolved by 6 weeks post-injury. Early and prolonged anti-calcitonin gene-related peptide mAb treatment inhibited the development of the cephalic tactile pain hypersensitivity in both the severe and repetitive subconcussive head impact models.

Conclusions

Severe head injury gives rise to a prolonged state of cephalic and extracephalic tactile pain hypersensitivity. These pain behaviors also develop following repetitive, subconcussive head impacts. Extended cephalic tactile pain hypersensitivity following severe and repetitive mild closed head injury are ameliorated by early and prolonged anti-calcitonin gene-related peptide mAb treatment, suggesting a mechanism linked to calcitonin gene-related peptide signaling, potentially of trigeminal origin.

中文翻译：

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闭合性头部损伤或重复性脑震荡下头部撞击的严重程度增加会增强大鼠模型中的创伤后头痛样行为。

介绍

创伤后头痛是颅脑外伤后最常见、使人虚弱且难以控制的症状之一。然而，由于缺乏临床前模型和对创伤后头痛的潜在机制了解不足，新治疗方法的发展受到阻碍。为了解决这些缺点，我们之前描述了使用 250 克体重下降的大鼠遭受单一轻度闭合性头部损伤的创伤后头痛样疼痛行为的发展。在这里，我们进行了一项后续研究，通过探索遭受单一但更严重的头部创伤 (450 g) 的雄性大鼠的头痛样疼痛行为的发展，进一步扩展用于研究创伤后头痛的临床前研究工具箱。在重复性的、脑震荡的头部撞击（150 克）之后。此外，

方法

成年雄性 Sprague Dawley 大鼠（总共 n = 138）使用负重装置或假手术进行弥漫性闭合性头部损伤。使用了三种损伤范例：单次击打，使用 450 克或 150 克的重量下降，以及间隔 72 小时进行的三个连续的 150 克重量下降事件。在头部外伤后长达 42 天，评估了开放领域活动的变化以及头和头外触觉疼痛超敏反应的发展。在 450 g 损伤或第三次 150 g 体重下降后立即开始全身施用抗降钙素基因相关肽 mAb 或其对照 IgG (30 mg/kg)，随后每 6 天给予额外剂量。

结果

遭受 450 g 闭合性头部损伤的大鼠表现出站立的急剧减少和趋向性增加，以及在受伤后 6 周内消退的头部触觉痛过敏。受伤的动物还表现出延迟和延长的脑外触觉痛超敏反应，这种超敏反应在受伤后 6 周仍然存在。使用 150 克体重下降的重复性脑震荡头部撞击，但不是单一事件，导致垂直后仰减少以及头和头外触觉疼痛超敏反应在受伤后 6 周内消退。早期和长时间的抗降钙素基因相关肽 mAb 治疗抑制了严重和重复性脑震荡头部撞击模型中头部触觉疼痛超敏反应的发展。

结论

严重的头部损伤会导致长期的头部和头部外触觉疼痛超敏反应。这些疼痛行为也会在重复的、脑震荡的头部撞击后发展。早期和长期抗降钙素基因相关肽单克隆抗体治疗可改善重度和重复性轻度闭合性颅脑损伤后延长的头部触觉疼痛超敏反应，这表明与降钙素基因相关肽信号传导相关的机制可能来自三叉神经。