Romozzi Marina, Scipioni Lucia, Di Tella Sonia, Silveri Maria Caterina, Cupini Letizia Maria, Vollono Catello, Maccarrone Mauro, Calabresi Paolo
Dipartimento Universitario di Neuroscienze, Università Cattolica del Sacro Cuore, Rome, Italy.
Neurologia, Dipartimento di Scienze dell'invecchiamento, Neurologiche, Ortopediche e della Testa-Collo, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy.
Cephalalgia. 2025 Jul;45(7):3331024251314460. doi: 10.1177/03331024251314460. Epub 2025 Jul 2.
BackgroundThe endocannabinoid system (ECS) is one of the key endogenous systems regulating pain. Preclinical and clinical evidence suggests a dysregulation of the ECS in patients with migraine. The present study aimed to characterize the main ECS components in patients with chronic migraine and medication overuse headache (MOH) and episodic migraine (EM) at the gene expression level compared to healthy controls (HC) and to correlate the findings with psychopathological scales.MethodsIn this cross-sectional study, consecutive patients with a diagnosis of EM and MOH were enrolled. Fatty acid amide hydrolase (FAAH) was assayed through quantitative enzyme-linked immunosorbent assay kits. The gene expression of ECS components (FAAH, -arachidonoyl phosphatidylethanolamine-specific phospholipase D (NAPE-PLD) and -acylethanolamine acid amidase (NAAA) enzymes, cannabinoid (CB) receptors, CB and CB, transient receptor potential vanilloid type 1 (TRPV1) and peroxisome proliferator-activated receptor (PPAR)ɑ receptors was assayed in peripheral blood mononuclear cells through a real-time quantitative PCR. Clinical data including Migraine Disability Assessment (MIDAS) and Headache Impact Test-6 (HIT-6) were collected. Psychopathological status was assessed through the Hamilton Anxiety Rating Scale (HAM-A), the Hamilton Rating Scale for Depression (HAM-D) and the Toronto Alexithymia Scale (TAS-20).ResultsThe study included 31 patients (15 with EM, 16 with MOH) and 14 HC. The gene expression of FAAH, an enzyme involved in the degradation of the main endocannabinoid, was significantly lower in MOH patients (0.0002 ± 0.0002) than in EM patients (0.0008 ± 0.0006) ( = 0.005). There were no significant differences in gene expression among EM, MOH and HC groups for NAPE-PLD, NAAA, CB, CB, TRPV1 and PPARɑ. The levels of FAAH protein expression were significantly higher in MOH (2.9517 ± 2.2006 pg/μg) compared to EM patients (0.9225 ± 0.6878 pg/μg) ( = 0.025). In the clinical group (EM and MOH), we found a significant negative correlation between FAAH gene expression and FAAH enzyme protein ( = 0.014); FAAH gene expression negatively correlated with HIT-6 ( = 0.003) and MIDAS scores ( = 0.048), as well with all psychopathological scales, in more detail with TAS-20 ( = 0.029), HAM-A ( = 0.040) and HAM-D ( = 0.028).ConclusionsFAAH undergoes specific alterations in patients with MOH at gene expression levels, suggesting its potential as a blood biomarker for this condition. FAAH gene expression is possibly related to psychiatric comorbidities in migraine patients.
背景
内源性大麻素系统（ECS）是调节疼痛的关键内源性系统之一。临床前和临床证据表明偏头痛患者的ECS存在失调。本研究旨在在基因表达水平上，与健康对照（HC）相比，对慢性偏头痛、药物过度使用性头痛（MOH）和发作性偏头痛（EM）患者的主要ECS成分进行特征描述，并将研究结果与心理病理学量表相关联。
方法
在这项横断面研究中，纳入了连续诊断为EM和MOH的患者。通过定量酶联免疫吸附测定试剂盒检测脂肪酸酰胺水解酶（FAAH）。通过实时定量PCR在外周血单核细胞中检测ECS成分（FAAH、N-花生四烯酰磷脂酰乙醇胺特异性磷脂酶D（NAPE-PLD）和N-酰基乙醇胺酸酰胺酶（NAAA）、大麻素（CB）受体CB1和CB2、瞬时受体电位香草酸亚型1（TRPV1）和过氧化物酶体增殖物激活受体（PPAR）α受体）的基因表达。收集包括偏头痛残疾评估（MIDAS）和头痛影响测试-6（HIT-6）在内的临床数据。通过汉密尔顿焦虑评定量表（HAM-A）、汉密尔顿抑郁评定量表（HAM-D）和多伦多述情障碍量表（TAS-20）评估心理病理状态。
结果
该研究纳入了31例患者（15例EM患者，16例MOH患者）和14例HC。参与主要内源性大麻素降解的FAAH酶的基因表达在MOH患者中（0.0002±0.0002）显著低于EM患者（0.0008±0.0006）（P = 0.005）。在EM、MOH和HC组之间，NAPE-PLD、NAAA、CB1、CB2、TRPV1和PPARα的基因表达没有显著差异。与EM患者（0.9225±0.6878 pg/μg）相比，MOH患者中FAAH蛋白表达水平显著更高（2.9517±2.2006 pg/μg）（P = 0.025）。在临床组（EM和MOH）中，我们发现FAAH基因表达与FAAH酶蛋白之间存在显著负相关（P = 0.014）；FAAH基因表达与HIT-6（P = 0.003）和MIDAS评分（P = 0.048）呈负相关，也与所有心理病理学量表呈负相关，更具体地与TAS-20（P = 0.029）、HAM-A（P = 0.040）和HAM-D（P = 0.028）呈负相关。
结论
FAAH在MOH患者的基因表达水平上发生特异性改变提示其作为这种疾病血液生物标志物的潜力。FAAH基因表达可能与偏头痛患者的精神共病有关。
