Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Centre, Harvard Medical School, Boston, MA, USA.
Teva Biologics, Redwood City, CA, USA.
Cephalalgia. 2020 Jun;40(7):748-760. doi: 10.1177/0333102420907597. Epub 2020 Feb 20.
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.
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).
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.
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.
据认为，女性在遭受创伤性头部损伤或脑震荡后，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颅脑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，以探索雌性大鼠在接受相同颅脑外伤方案后，创伤后头痛样行为的发展以及这些头痛治疗方法的有效性。
成年雌性 Sprague Dawley 大鼠通过重物坠落装置（n = 126）或假手术（n = 28）接受轻度闭合性颅脑损伤。使用 von Frey 单丝评估头皮和颅外触觉疼痛敏感性的变化，对头痛和疼痛相关行为进行特征描述。通过测试腹腔内给予低剂量甘油三硝酸酯（100μg/kg）对内源性头痛/偏头痛触发因素的影响来检测敏感性。治疗方法包括急性全身给予舒马曲坦（1mg/kg）和重复全身给予抗降钙素基因相关肽单克隆抗体（30mg/kg）。在新的雌性（n = 38）和雄性（n = 36）大鼠队列中，在基线和颅脑损伤后不同时间点测量降钙素基因相关肽的血清水平。
接受轻度闭合性颅脑损伤的雌性大鼠出现头皮机械性痛觉过敏，仅限于头区，4 周后缓解。舒马曲坦治疗可改善头区疼痛过敏，但对早期和长期的抗降钙素基因相关肽单克隆抗体治疗无反应。在颅脑损伤引起的头区过敏缓解后，给予甘油三硝酸酯可引起头区和颅外疼痛过敏的重新出现和显著加剧，舒马曲坦可抑制这种过敏，而抗降钙素基因相关肽治疗仅部分抑制这种过敏。颅脑损伤后 7 天，雌性大鼠降钙素基因相关肽的血清水平升高，但雄性大鼠没有升高。
轻度闭合性颅脑损伤后，创伤后头痛样疼痛行为的发展以及大鼠对治疗的反应存在性别差异。与之前研究中雄性大鼠的数据相比，雌性大鼠表现出头区痛觉过敏持续时间延长、对头痛触发因素的反应增强以及早期和长期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外周降钙素基因相关肽信号传导无关的机制有关。
