INTRODUCTION Females are thought to have increased risk of developing post-traumatic headache following a traumatic head injury or concussion. However, the processes underlying this susceptibility remain unclear. We previously demonstrated the development of post-traumatic headache-like pain behaviors in a male rat model of mild closed head injury, along with the ability of sumatriptan and an anti-calcitonin-gene-related peptide monoclonal antibody to ameliorate these behaviors. Here, we conducted a follow-up study to explore the development of post-traumatic headache-like behaviors and the effectiveness of these headache therapies in females subjected to the same head trauma protocol. METHODS Adult female Sprague Dawley rats were subjected to a mild closed head injury using a weight-drop device (n = 126), or to a sham procedure (n = 28). Characterization of headache and pain related behaviors included assessment of changes in cutaneous cephalic and extracephalic tactile pain sensitivity, using von Frey monofilaments. Sensitivity to headache/migraine triggers was tested by examining the effect of intraperitoneal administration of a low dose of glyceryl trinitrate (100 µg/kg). Treatments included acute systemic administration of sumatriptan (1 mg/kg) and repeated systemic administration of a mouse anti-calcitonin gene-related peptide monoclonal antibody (30 mg/kg). Serum levels of calcitonin gene-related peptide were measured at baseline and at various time points post head injury in new cohorts of females (n = 38) and males (n = 36). RESULTS Female rats subjected to a mild closed head injury developed cutaneous mechanical hyperalgesia, which was limited to the cephalic region and was resolved 4 weeks later. Cephalic pain hypersensitivity was ameliorated by treatment with sumatriptan but was resistant to an early and prolonged treatment with the anti-calcitonin gene-related peptide monoclonal antibody. Following the resolution of the head injury-evoked cephalic hypersensitivity, administration of glyceryl trinitrate produced a renewed and pronounced cephalic and extracephalic pain hypersensitivity that was inhibited by sumatriptan, but only partially by the anti-calcitonin gene-related peptide treatment. Calcitonin gene-related peptide serum levels were elevated in females but not in males at 7 days post head injury. CONCLUSIONS Development of post-traumatic headache-like pain behaviors following a mild closed head injury, and responsiveness to treatment in rats is sexually dimorphic. When compared to the data obtained from male rats in the previous study, female rats display a prolonged state of cephalic hyperalgesia, increased responsiveness to a headache trigger, and a poorer effectiveness of an early and prolonged anti-calcitonin gene-related peptide treatment. The increased risk of females to develop post-traumatic headache may be linked to enhanced responsiveness of peripheral and/or central pain pathways and a mechanism independent of peripheral calcitonin gene-related peptide signaling.

中文翻译：

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在轻度闭合性头部损伤后，雌性大鼠的创伤后头痛样行为增强，外周 CGRP 的作用减弱。

引言 女性被认为在头部外伤或脑震荡后发生创伤后头痛的风险增加。然而，这种易感性背后的过程仍不清楚。我们之前在轻度闭合性头部损伤的雄性大鼠模型中证明了创伤后头痛样疼痛行为的发展，以及舒马曲坦和抗降钙素基因相关肽单克隆抗体改善这些行为的能力。在这里，我们进行了一项后续研究，以探索创伤后头痛样行为的发展以及这些头痛疗法在遭受相同头部创伤方案的女性中的有效性。方法 成年雌性 Sprague Dawley 大鼠使用负重装置（n = 126）或假手术（n = 28）遭受轻度闭合性头部损伤。头痛和疼痛相关行为的表征包括使用 von Frey 单丝评估皮肤头部和头部外触觉疼痛敏感性的变化。通过检查腹膜内施用低剂量硝酸甘油 (100 µg/kg) 的效果来测试对头痛/偏头痛触发因素的敏感性。治疗包括急性全身给药舒马曲坦 (1 mg/kg) 和反复全身给药小鼠抗降钙素基因相关肽单克隆抗体 (30 mg/kg)。在新的女性（n = 38）和男性（n = 36）队列中，在基线和头部受伤后的不同时间点测量血清降钙素基因相关肽水平。结果 遭受轻度闭合性头部损伤的雌性大鼠出现皮肤机械痛觉过敏，仅限于头部区域，并在 4 周后解决。用舒马曲坦治疗可改善头部疼痛超敏反应，但对抗降钙素基因相关肽单克隆抗体的早期和长期治疗具有抗性。在头部损伤引起的头部超敏反应消退后，三硝酸甘油酯的给药产生了一种新的和明显的头部和头外疼痛超敏反应，该超敏反应被舒马曲坦抑制，但仅部分被抗降钙素基因相关肽治疗抑制。降钙素基因相关肽血清水平在女性头部受伤后 7 天升高，但在男性中没有升高。结论 轻度闭合性头部损伤后出现创伤后头痛样疼痛行为，大鼠对治疗的反应是性别二态的。与之前研究中从雄性大鼠获得的数据相比，雌性大鼠表现出长期的头部痛觉过敏状态，对头痛触发的反应增加，以及早期和长期抗降钙素基因相关肽治疗的效果较差。女性发生创伤后头痛的风险增加可能与外周和/或中枢疼痛通路的反应增强以及与外周降钙素基因相关肽信号无关的机制有关。早期和长期的抗降钙素基因相关肽治疗效果较差。女性发生创伤后头痛的风险增加可能与外周和/或中枢疼痛通路的反应增强以及与外周降钙素基因相关肽信号无关的机制有关。早期和长期的抗降钙素基因相关肽治疗效果较差。女性发生创伤后头痛的风险增加可能与外周和/或中枢疼痛通路的反应增强以及与外周降钙素基因相关肽信号无关的机制有关。