Wen Jie, Tanaka Mikiei, Zhang Yumin
Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD, 20814, USA.
J Headache Pain. 2025 Aug 12;26(1):183. doi: 10.1186/s10194-025-02116-x.
Posttraumatic headache (PTH) is a common and debilitating consequence of traumatic brain injury (TBI), characterized by neuroinflammation and pain hypersensitivity. Current treatments are limited, and novel therapeutics are needed. Indomethacin morpholinamide (IMMA), a substrate-selective cyclooxygenase-2 (COX-2) inhibitor, enhances endocannabinoid signaling without disrupting prostaglandin homeostasis and may offer a mechanistically distinct approach to managing PTH.
Male C57BL/6J mice were subjected to repetitive mild TBI (rmTBI) using the Closed-Head Impact Model of Engineered Rotational Acceleration (CHIMERA) and treated with IMMA (10 mg/kg, i.p.) daily for 7 days post-injury. Mechanical allodynia was assessed using von Frey stimulation of the periorbital region. Neuroinflammation was evaluated through immunohistochemistry in the trigeminal ganglion (TG) and trigeminal nucleus caudalis (TNC). Endocannabinoid and prostaglandin levels were quantified by mass spectrometry and enzyme immunoassay, respectively.
IMMA significantly reduced rmTBI-induced periorbital allodynia, microglial and astrocyte activation, and CGRP expression in the TG and TNC. It also preserved meningeal mast cell integrity and elevated cortical anandamide (AEA) levels without altering prostaglandin E₂ (PGE₂) production, supporting a mechanism that enhances cannabinoid signaling while sparing COX-2-mediated prostaglandin synthesis.
IMMA effectively attenuates neuroinflammation and pain hypersensitivity in the acute phase of PTH through a distinct mechanism that preserves endocannabinoid tone without suppressing physiological prostaglandins. While these results highlight its promise as a novel therapeutic strategy, further studies are warranted to determine its efficacy during the chronic phase of PTH and across anatomically targeted regions.
创伤后头痛（PTH）是创伤性脑损伤（TBI）常见且使人衰弱的后果，其特征为神经炎症和疼痛超敏反应。目前的治疗方法有限，需要新的治疗手段。吲哚美辛吗啉酰胺（IMMA）是一种底物选择性环氧合酶-2（COX-2）抑制剂，可增强内源性大麻素信号传导，同时不破坏前列腺素稳态，可能为PTH的治疗提供一种机制上不同的方法。
使用工程旋转加速度闭合性头部撞击模型（CHIMERA）对雄性C57BL/6J小鼠进行重复性轻度TBI（rmTBI），并在损伤后每天腹腔注射IMMA（10 mg/kg），持续7天。使用von Frey刺激眶周区域评估机械性异常性疼痛。通过三叉神经节（TG）和三叉神经尾核（TNC）的免疫组织化学评估神经炎症。分别通过质谱和酶免疫测定法定量内源性大麻素和前列腺素水平。
IMMA显著降低了rmTBI诱导的眶周异常性疼痛、小胶质细胞和星形胶质细胞活化以及TG和TNC中的降钙素基因相关肽（CGRP）表达。它还保持了脑膜肥大细胞的完整性，并提高了皮质花生四烯酸乙醇胺（AEA）水平，同时不改变前列腺素E₂（PGE₂）的产生，支持了一种增强大麻素信号传导同时保留COX-2介导的前列腺素合成的机制。
IMMA通过一种独特的机制有效地减轻了PTH急性期的神经炎症和疼痛超敏反应，该机制保留了内源性大麻素张力而不抑制生理性前列腺素。虽然这些结果突出了其作为一种新的治疗策略的前景，但仍需要进一步研究以确定其在PTH慢性期以及跨解剖学靶向区域的疗效。
