Department of Pharmacology, College of Medicine, University of Arizona, Tucson, Arizona, USA.
Department of Pharmacology, Federal University of Parana, Curitiba, Parana, Brazil.
Cephalalgia. 2021 May;41(6):749-759. doi: 10.1177/0333102420981688. Epub 2021 Feb 20.
Determine the role of calcitonin-gene related peptide in promoting post-traumatic headache and dysregulation of central pain modulation induced by mild traumatic brain injury in mice.
Mild traumatic brain injury was induced in lightly anesthetized male C57BL/6J mice by a weight drop onto a closed and unfixed skull, which allowed free head rotation after the impact. We first determined possible alterations in the diffuse noxious inhibitory controls, a measure of net descending pain inhibition called conditioned pain modulation in humans at day 2 following mild traumatic brain injury. Diffuse noxious inhibitory control was assessed as the latency to a thermally induced tail-flick that served as the test stimulus in the presence of right forepaw capsaicin injection that provided the conditioning stimulus. Post-traumatic headache-like behaviors were assessed by the development of cutaneous allodynia in the periorbital and hindpaw regions after mild traumatic brain injury. We then determined if intraperitoneal fremanezumab, an anti-calcitonin-gene related peptide monoclonal antibody or vehicle administered 2 h after sham or mild traumatic brain injury induction could alter cutaneous allodynia or diffuse noxious inhibitory control responses on day 2 post mild traumatic brain injury.
In naïve and sham mice, capsaicin injection into the forepaw elevated the latency to tail-flick, reflecting the antinociceptive diffuse noxious inhibitory control response. Periorbital and hindpaw cutaneous allodynia, as well as a loss of diffuse noxious inhibitory control, was observed in mice 2 days after mild traumatic brain injury. Systemic treatment with fremanezumab blocked mild traumatic brain injury-induced cutaneous allodynia and prevented the loss of diffuse noxious inhibitory controls in mice subjected to a mild traumatic brain injury.
Sequestration of calcitonin-gene related peptide in the initial stages following mild traumatic brain injury blocked the acute allodynia that may reflect mild traumatic brain injury-related post-traumatic headache and, additionally, prevented the loss of net descending inhibition within central pain modulation pathways. As loss of conditioned pain modulation has been linked to multiple persistent pain conditions, dysregulation of descending modulatory pathways may contribute to the persistence of post-traumatic headache. Additionally, evaluation of the conditioned pain modulation/diffuse noxious inhibitory controls response may serve as a biomarker of vulnerability for chronic/persistent pain. These findings suggest that early anti-calcitonin-gene related peptide intervention has the potential to be effective both for the treatment of mild traumatic brain injury-induced post-traumatic headache, as well as inhibiting mechanisms that may promote post-traumatic headache persistence.
确定降钙素基因相关肽在促进轻度创伤性脑损伤后小鼠创伤后头痛和中枢疼痛调节失调中的作用。
通过将重量施加到闭合且未固定的颅骨上，使轻度麻醉的雄性 C57BL/6J 小鼠受到轻度创伤性脑损伤，从而在允许头部自由旋转的情况下诱导轻度创伤性脑损伤。我们首先确定在轻度创伤性脑损伤后第 2 天，弥漫性有害抑制控制（一种称为条件性疼痛调制的人类下行疼痛抑制的净测量）可能发生的变化。弥漫性有害抑制控制作为在右前爪辣椒素注射提供条件刺激的情况下，热诱导的尾巴拍打测试刺激的潜伏期来评估。创伤后头痛样行为通过轻度创伤性脑损伤后眶周和后爪区域的皮肤感觉过敏来评估。然后，我们确定在假手术或轻度创伤性脑损伤诱导后 2 小时内腹膜内给予抗降钙素基因相关肽单克隆抗体弗雷马泽umab 或载体是否可以改变轻度创伤性脑损伤后第 2 天的皮肤感觉过敏或弥漫性有害抑制控制反应。
在未受伤和假手术的小鼠中，前爪中的辣椒素注射会提高尾巴拍打测试的潜伏期，反映出抗伤害性的弥漫性有害抑制控制反应。在轻度创伤性脑损伤后 2 天，观察到眶周和后爪皮肤感觉过敏以及弥漫性有害抑制控制丧失。全身性给予弗雷马泽umab 可阻断轻度创伤性脑损伤引起的皮肤感觉过敏，并防止轻度创伤性脑损伤小鼠中弥漫性有害抑制控制的丧失。
在轻度创伤性脑损伤后早期，降钙素基因相关肽的隔离阻断了可能反映轻度创伤性脑损伤相关创伤后头痛的急性感觉过敏，并且还防止了中枢疼痛调节途径中下行抑制的丧失。由于条件性疼痛调制的丧失与多种持续性疼痛状况有关，因此下行调节途径的失调可能导致创伤后头痛的持续存在。此外，对条件性疼痛调制/弥漫性有害抑制控制反应的评估可作为慢性/持续性疼痛易感性的生物标志物。这些发现表明，早期抗降钙素基因相关肽干预既有可能有效治疗轻度创伤性脑损伤引起的创伤后头痛，又能抑制可能促进创伤后头痛持续存在的机制。
