Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD, 20814, USA.
J Headache Pain. 2024 Jul 16;25(1):115. doi: 10.1186/s10194-024-01817-z.
Posttraumatic headache (PTH) is a common and debilitating symptom following repetitive mild traumatic brain injury (rmTBI), and it mainly resembles a migraine-like phenotype. While modulation of the endocannabinoid system (ECS) is effective in treating TBI and various types of pain including migraine, the role of augmentation of endocannabinoids in treating PTH has not been investigated.
Repetitive mild TBI was induced in male C57BL/6J mice using the non-invasive close-head impact model of engineered rotational acceleration (CHIMERA). Periorbital allodynia was assessed using von Frey filaments and determined by the "Up-Down" method. Immunofluorescence staining was employed to investigate glial cell activation and calcitonin gene-related peptide (CGRP) expression in the trigeminal ganglion (TG) and trigeminal nucleus caudalis (TNC) of the rmTBI mice. Levels of 2-arachidonoyl glycerol (2-AG), anandamide (AEA), and arachidonic acid (AA) in the TG, medulla (including TNC), and periaqueductal gray (PAG) were measured by mass spectrometry. The therapeutic effect of endocannabinoid modulation on PTH was also assessed.
The rmTBI mice exhibited significantly increased cephalic pain hypersensitivity compared to the sham controls. MJN110, a potent and selective inhibitor of the 2-AG hydrolytic enzyme monoacylglycerol lipase (MAGL), dose-dependently attenuated periorbital allodynia in the rmTBI animals. Administration of CGRP at 0.01 mg/kg reinstated periorbital allodynia in the rmTBI animals on days 33 and 45 post-injury but had no effect in the sham and MJN110 treatment groups. Activation of glial cells along with increased production of CGRP in the TG and TNC at 7 and 14 days post-rmTBI were attenuated by MJN110 treatment. The anti-inflammatory and anti-nociceptive effects of MJN110 were partially mediated by cannabinoid receptor activation, and the pain-suppressive effect of MJN110 was completely blocked by co-administration of DO34, an inhibitor of 2-AG synthase. The levels of 2-AG in TG, TNC and PAG were decreased in TBI animals, significantly elevated and further reduced by the selective inhibitors of 2-AG hydrolytic and synthetic enzymes, respectively.
Enhancing endogenous levels of 2-AG appears to be an effective strategy for the treatment of PTH by attenuating pain initiation and transmission in the trigeminal pathway and facilitating descending pain inhibitory modulation.
创伤后头痛（PTH）是重复轻度创伤性脑损伤（rmTBI）后的一种常见且使人虚弱的症状，主要类似于偏头痛样表型。尽管内源性大麻素系统（ECS）的调节对治疗创伤性脑损伤和包括偏头痛在内的各种类型的疼痛有效，但增强内源性大麻素在治疗 PTH 中的作用尚未得到研究。
雄性 C57BL/6J 小鼠使用工程旋转加速度（CHIMERA）的无创近头部撞击模型诱导重复轻度 TBI。使用 von Frey 纤维评估眶周感觉过敏，并通过“上下”法确定。免疫荧光染色用于研究 rmTBI 小鼠三叉神经节（TG）和三叉神经尾核（TNC）中的神经胶质细胞激活和降钙素基因相关肽（CGRP）表达。通过质谱法测量 TG、延髓（包括 TNC）和导水管周围灰质（PAG）中 2-花生四烯酰甘油（2-AG）、花生四烯酸（AEA）和花生四烯酸（AA）的水平。还评估了内源性大麻素调节对 PTH 的治疗效果。
与假对照相比，rmTBI 小鼠表现出明显增加的头部疼痛过敏。强效和选择性 2-AG 水解酶单酰基甘油脂肪酶（MAGL）抑制剂 MJN110 剂量依赖性地减轻 rmTBI 动物的眶周感觉过敏。在损伤后 33 和 45 天，CGRP 以 0.01mg/kg 的剂量恢复了 rmTBI 动物的眶周感觉过敏，但在假手术和 MJN110 治疗组中没有效果。在 rmTBI 后 7 和 14 天，TG 和 TNC 中的神经胶质细胞激活和 CGRP 产生增加被 MJN110 治疗减轻。MJN110 的抗炎和抗伤害作用部分通过大麻素受体激活介导，并且 DO34（2-AG 合酶抑制剂）的共同给药完全阻断了 MJN110 的镇痛作用。在 TBI 动物中，TG、TNC 和 PAG 中的 2-AG 水平降低，选择性 2-AG 水解和合成酶抑制剂分别显著升高并进一步降低。
通过减弱三叉神经通路中的疼痛起始和传递以及促进下行疼痛抑制调节，增强内源性 2-AG 水平似乎是治疗 PTH 的有效策略。
