背景:创伤后头痛(PTH)是重复性轻度创伤性脑损伤(rmTBI)后常见且使人衰弱的症状,它主要类似于偏头痛样表型。虽然调节内源性大麻素系统(ECS)可有效治疗TBI和各种类型的疼痛,包括偏头痛,内源性大麻素在治疗PTH中的作用尚未得到研究.
方法:使用工程旋转加速度(CHIMERA)的非侵入性闭头撞击模型,在雄性C57BL/6J小鼠中诱导了重复性轻度TBI。使用vonFrey丝评估眶周异常性疼痛,并通过“上下”方法确定。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)中神经胶质细胞活化和降钙素基因相关肽(CGRP)的表达。2-花生四酰基甘油(2-AG)的水平,anandamide(AEA),TG中的花生四烯酸(AA),髓质(包括TNC),通过质谱测量和周围导水管灰色(PAG)。还评估了内源性大麻素调节对PTH的治疗效果。
结果:与假手术对照相比,rmTBI小鼠表现出显著增加的头痛超敏反应。MJN110,2-AG水解酶单酰基甘油脂肪酶(MAGL)的有效和选择性抑制剂,剂量依赖性地减轻rmTBI动物的眶周异常性疼痛。以0.01mg/kg的CGRP给药在损伤后第33天和第45天恢复rmTBI动物的眶周异常性疼痛,但在假手术和MJN110治疗组中没有作用。在rmTBI后7天和14天,神经胶质细胞的活化以及TG和TNC中CGRP产生的增加被MJN110处理减弱。MJN110的抗炎和抗伤害性作用部分由大麻素受体激活介导,通过共同施用2-AG合酶抑制剂DO34,MJN110的疼痛抑制作用被完全阻断。TG中2-AG的水平,TNC和PAG在TBI动物中降低,2-AG水解和合成酶的选择性抑制剂显着升高并进一步降低,分别。
结论:增强内源性2-AG水平似乎是治疗PTH的有效策略,通过减弱三叉神经途径中的疼痛开始和传递,并促进疼痛抑制调节下降。
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.