Journal of Headache and Pain最新文献

{"title":"Fibroblast reprogramming in the dura mater of NTG-induced migraine-related chronic hypersensitivity model drives monocyte infiltration via Angptl1-dependent stromal signaling.","authors":"Guangyu Guo, Lei Zhang, Xuyang Liu, Yiping Deng, Peiyu Wu, Ruofan Zhao, Wei Wang","doi":"10.1186/s10194-025-02058-4","DOIUrl":"https://doi.org/10.1186/s10194-025-02058-4","url":null,"abstract":"<p><strong>Background: </strong>Migraine, characterized by recurrent episodes of severe headache, remains mechanistically enigmatic. While traditional theories emphasize trigeminovascular activation, the role of meningeal stromal-immune crosstalk in disease chronicity is poorly understood.</p><p><strong>Methods: </strong>A migraine-related chronic hypersensitivity model was utilized via intermittent intraperitoneal nitroglycerin (NTG, 10 mg/kg, every other day for 9 days) and peripheral mechanical hypersensitivity was assessed using von Frey filaments. Single-cell RNA sequencing (scRNA-seq) was performed on dura tissues to construct a cellular atlas of NTG-induced remodeling. These data were then integrated with migraine genome-wide association study (GWAS) risk genes, cell-cell interaction networks, and transcriptional regulation analysis to dissect NTG-driven meningeal remodeling.</p><p><strong>Results: </strong>The NTG-induced migraine-related chronic hypersensitivity model demonstrated sustained mechanical allodynia, as evidenced by significantly decreased paw withdrawal thresholds (p < 0.0001). Single-cell profiling of the dura mater revealed a 2.4-fold expansion of a pro-inflammatory fibroblast subpopulation (Fibro_c5: 1.9% in Vehicle vs. 4.6% in NTG group), which exhibited marked activation of TNF-α/NF-κB signaling pathways (normalized enrichment score [NES] = 1.83). Concomitantly, we observed an 82% increase in meningeal monocytes (5.7-10.4%) that showed preferential interaction with Fibro_c5 fibroblasts through Angptl1-mediated stromal-immune crosstalk (log2 fold change = 1.41). Regulatory network analysis identified Mafk as the upstream transcriptional regulator orchestrating Angptl1 expression in this pathological communication axis.</p><p><strong>Conclusion: </strong>Our study reveals that NTG reprograms meningeal fibroblasts to expand a pro-inflammatory fibroblast subtype, which drives migraine-related chronic hypersensitivity through TNF-α/NF-κB signaling and Angptl1-mediated monocyte crosstalk. The identified Mafk-Angptl1 axis presents a potential therapeutic target, though human validation remains essential.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":"26 1","pages":"130"},"PeriodicalIF":7.3,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144150768","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Validation of an 8-item self-administered questionnaire for assessing migraine-related sensory hypersensitivities (MHQ-8).","authors":"François Gabrielli, Melissa Zuel, Camille Magaud, Sophia Sickout-Arondo, Bruno Pereira, Jérémie Dassa, Solène De Gaalon, Geneviève Demarquay, Anne Donnet, Anne Ducros, Pierric Giraud, Evelyne Guégan-Massardier, Christian Lucas, Jérôme Mawet, Mitra Najjar, Caroline Roos, Elise K Van Obberghen, Christian Dualé, Radhouane Dallel, Xavier Moisset","doi":"10.1186/s10194-025-02067-3","DOIUrl":"10.1186/s10194-025-02067-3","url":null,"abstract":"<p><strong>Background: </strong>In addition to headache, migraine patients often experience sensory hypersensitivity to external stimuli. While photophobia and phonophobia are part of the diagnostic criteria of migraine, many patients also exhibit cutaneous allodynia and osmophobia. However, the presence and intensity of these four hypersensitivities are rarely assessed systematically and simultaneously due to the lack of a simple and rapid self-report questionnaire.</p><p><strong>Methods: </strong>We have identified existing questionnaires for allodynia, photophobia and phonophobia and selected one of each, that were translated in French and validated (according to COSMIN's recommendations). We also proposed a 2-item questionnaire (presence and intensity) for each of these 3 hypersensitivities plus osmophobia, resulting in the 8-item Migraine Hypersensitivity Questionnaire (MHQ-8) exploring these four hypersensitivities. In addition, the headache impact test (HIT-6), the migraine disability assessment (MIDAS) and the hospital anxiety and depression scale (HADS) were also answered. The survey was conducted in Pain and Neurology departments during specialised consultations for headaches. Content validity, structural validity, internal consistency, transcultural validity, reliability, criterion validity, construct validity and responsiveness were tested. Confirmatory factor analysis (CFA) was used to test the dimensionality of the questionnaires.</p><p><strong>Results: </strong>The study sample consisted in N = 329 patients with a mean age of 43.7 ± 13.2 and a mean number of 10.2 ± 7.0 migraine days per month; 84% of them were women and 27% had chronic migraine. Overall, 312 to 327 questionnaires were usable for the hypersensitivity questionnaires. The reliability of the MHQ-8 was good to excellent with a Cronbach's alpha of α = 0.88 (photophobia), α = 0.89 (phonophobia), α = 0.91 (allodynia), α = 0.95 (osmophobia), and α = 0.85 for the whole questionnaire. The intraclass correlation coefficient assessing test-retest reliability was 0.83, 0.77, 0.87, and 0.90, respectively; it was 0.88 for the whole questionnaire. The factor analysis on the MHQ-8 items showed excellent exploratory results, and the indicators of the CFA showed good performances with CFI and TLI at 0.999, RMSEA at 0.054 and SRMR at 0.021.</p><p><strong>Conclusions: </strong>The MHQ-8 developed in this study is valid and reliable. It serves as a new diagnostic tool for the four sensory hypersensitivities that can occur during migraine attacks and may be useful in both clinical research and daily practice.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":"26 1","pages":"128"},"PeriodicalIF":7.3,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144142742","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association between headaches and lifestyle factors and physical and mental symptoms among 63,071 workers at a Japanese information technology company.","authors":"Masako Yokoyama, Hisaka Igarashi, Hirohisa Kato, Tetsuji Yokoyama, Hiroshi Ebihara, Yasuhiro Azuma, Fumihiko Sakai, Hitoshi Miyake, Satoko Nagumo","doi":"10.1186/s10194-025-02065-5","DOIUrl":"10.1186/s10194-025-02065-5","url":null,"abstract":"<p><strong>Background: </strong>Headaches are common and can significantly affect working conditions. To reduce their occurrence at work, identifying factors associated with headaches is important. We aimed to investigate the association between headaches and lifestyle factors, as well as physical and mental symptoms, among workers at the Fujitsu Group, a Japanese information technology company, to identify factors contributing to workplace headaches.</p><p><strong>Methods: </strong>The results of a 2022 Stress Check Survey questionnaire (mandated by Japanese occupational law requirements) were evaluated concerning 63,071 Fujitsu Group workers (men, n = 50,360; [mean age ± standard deviation, 45.6 ± 10.7 years]; women, n = 12,711 [41.8 ± 11.5 years]).</p><p><strong>Results: </strong>The headache rates according to frequency category (seldom, sometimes, often, and almost always) were as follows: men, 48.8%, 34.2%, 13.9%, and 3.1%, respectively, and women, 33.6%, 39.9%, 21.0%, and 5.5%, respectively. Multiple logistic regression analysis of lifestyle factors showed that the odds ratio (OR [95% confidence interval]) for headache (sometimes, often, or almost always) was highest in the presence of \"high stress levels\" (men, 7.13 [6.57-7.73]; women, 8.79 [7.07-10.94]). Other lifestyle factors included \"seldom exercising\" (men, 1.47 [1.36-1.60]; women, 1.55 [1.27-1.89]) and \"weekday sitting time > 12 h\" (men, 1.35 [1.27-1.43]; women, 1.61 [1.40-1.84]). The population attributable fraction for \"exercise habits,\" \"high stress levels,\" and \"sitting time\" in men was 26.1%, 8.4%, and 5.2%, respectively, and 30.5%, 5.4%, and 4.9%, in women, respectively. Further analysis regarding physical and mental symptoms showed that the ORs for headache increased with the presence of \"stiff shoulders\" (men, 3.65 [3.37-3.96]; women, 5.08 [4.26-6.05]), \"insomnia\" (men, 2.71 [2.41-3.05]; women, 2.61 [2.00-3.41]), \"eye strain\" (men, 2.62 [2.40-2.86]; women, 2.31 [1.93-2.76]), \"depression\" (men, 2.35 [2.06-2.69]; women, 2.35 [1.76-3.14]), \"back pain\" (men, 1.66 [1.53-1.80]; women, 2.08 [1.75-2.40]), and \"anxiety\" (men, 1.32 [1.18-1.48]; women, 1.55 [1.20-2.00]).</p><p><strong>Conclusions: </strong>This large-scale survey among Japanese workers revealed the strength of the association between headaches and various lifestyle factors, and physical and mental symptoms. These findings could guide workplace interventions to decrease headaches among workers.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":"26 1","pages":"129"},"PeriodicalIF":7.3,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144142695","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ergotamine enhances circadian amplitude and diurnally mitigates nitroglycerin-induced mechanical hypersensitivity.","authors":"Chorong Han, Hwayoung Baek, Ji Ye Lim, Eunju Kim, Celia K Tran, Emma Freeman, Zheng Chen, Seung-Hee Yoo, Mark J Burish","doi":"10.1186/s10194-025-02008-0","DOIUrl":"10.1186/s10194-025-02008-0","url":null,"abstract":"<p><strong>Background: </strong>Cluster headache and migraine have a circadian timing of attacks and are linked to the trigeminovascular system. Recently the trigeminal ganglion was found to have a strong circadian rhythm, with the serotonin 2A receptor identified as a clock-controlled gene. Ergotamine is an acute treatment for cluster headache and migraine, acts on the trigeminal ganglion, and is a serotonin 2A receptor agonist. The circadian properties of ergotamine are unknown.</p><p><strong>Methods: </strong>We performed real-time bioluminescence monitoring and qPCR of Per2::LucSV reporter mouse fibroblast cultures after treatment with ergotamine. We examined receptor effects by treating Per2::LucSV fibroblast cultures with ergotamine and one of several serotoninergic, adrenergic, and/or dopaminergic receptor antagonists. Next, we treated Per2::LucSV reporter mouse trigeminal ganglion explants with ergotamine and monitored circadian reporter rhythms; finally we measured hindpaw sensitivity in a nitroglycerin chronic headache mouse model and administered ergotamine at two different times to examine a chronotherapeutic effect on pain behavior.</p><p><strong>Results: </strong>Ergotamine caused a more than two-fold increase in the amplitude of Per2::LucSV fibroblasts without a change in period length; amplitude enhancement was also seen for expression of Clock, Bmal1, Period3, Cryptochrome2, Rev-erbα, and Rev-erbβ. Ergotamine's effect on circadian amplitude was dampened by the serotonin-1B/1D receptor antagonist GR127935, the serotonin-1D receptor antagonist BRL1557, the serotonin-1A/1B/2A/2B/2C, alpha1A-adrenergic, and dopamine D1-4 receptor antagonist asenapine, and the serotonin-2C receptor antagonist SB242084. In contrast to serotonin receptor antagonists, ergotamine's effects on clock amplitude were unchanged by other serotonin antagonists or by selective adrenergic or dopaminergic receptor antagonists, suggesting that ergotamine's amplitude effect is mediated by serotonin receptor activation. Furthermore, trigeminal ganglion explant cultures treated with ergotamine showed a significant increase in amplitude without a change in period. Finally, in the nitroglycerin chronic headache mouse model, ergotamine significantly raised hindpaw thresholds when administered during the daytime (ZT4) but not at night (ZT16).</p><p><strong>Conclusions: </strong>Ergotamine has substantial circadian rhythm modification effects in both cellular and animal models. Ergotamine's circadian effects appear to be mediated through serotonin 1D and 2C receptors, providing a rationale for why sub-psychedelic doses of psilocybin (which induces psychedelic responses through the serotonin 2A receptor) might be effective. Ergotamine's peak effect on hindpaw thresholds at ZT4 suggests that ergotamine may be more effective at certain times of day.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":"26 1","pages":"127"},"PeriodicalIF":7.3,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12100948/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144132422","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nuclear paraspeckle assembly transcript 1 promotes photophobia behavior in mice via miR-196a-5p/Trpm3 coupling.","authors":"Zhuoan Huang, Xingshen Li, Xiaolin Wang, Jiaqi Wu, Ziyang Gong, Sulev Kõks, Minyan Wang","doi":"10.1186/s10194-025-02057-5","DOIUrl":"10.1186/s10194-025-02057-5","url":null,"abstract":"<p><strong>Background: </strong>The long noncoding RNA, NEAT1, is recognized as a key regulator of proinflammatory gene expression; Yet, its functional role in migraine remains unexplored, despite the central role of neuroinflammatory mechanisms in migraine pathophysiology. This study examines the implication of NEAT1 in the trigeminal ganglion activation, which underlies photophobia associated with migraine.</p><p><strong>Methods: </strong>Light aversion behavior was induced by intranasal injection of the TRPA1 activator, umbellulone. Male mouse behavior was assessed by the total time the mouse stays in the light between the dark and light compartments. To gain insight to the NEAT1-mediated photophobia mechanism, gene expression of candidate genes and non-coding RNAs interactions were assessed using RNA-sequencing, qPCR analysis, histology and dual-luciferase reporter gene assay.</p><p><strong>Results: </strong>NEAT1 was upregulated in the trigeminal ganglion of male photophobia mice; Downregulation of NEAT1 by intravenous injection of shNEAT1 adeno-associated virus vectors attenuated NEAT1 expression and alleviated photophobia-like behavior in mice. The elevated NEAT1 expression in the trigeminal ganglion of photophobia mice corresponds to the downregulation of miR-196a-5p and upregulation Trpm3 RNA level. Predicted analysis suggested NEAT1/miR-196a-5p ceRNA network exists in photophobia mice. Indeed, knocking down NEAT1 upregulated miR-196a-5p, whilst downregulated Trpm3 gene expression level, in the trigeminal ganglion of photophobia mice. Further investigation using dual-luciferase reporter gene assay identified NEAT1 interacting with miR-196a-5p, whilst miR-196a-5p interacting with Trpm3. Similar to knocking down NEAT1, TRPM3 inhibition reduced photophobia-like behavior.</p><p><strong>Conclusion: </strong>We conclude that NEAT1 is critical for promoting photophobia behavior via miR-196a-5p/Trpm3 coupling.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":"26 1","pages":"118"},"PeriodicalIF":7.3,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12096706/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144119873","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unravelling the gut-brain connection: a systematic review of migraine and the gut microbiome.","authors":"Caroline W Mugo, Ella Church, Richard D Horniblow, Susan P Mollan, Hannah Botfield, Lisa J Hill, Alexandra J Sinclair, Olivia Grech","doi":"10.1186/s10194-025-02039-7","DOIUrl":"10.1186/s10194-025-02039-7","url":null,"abstract":"<p><strong>Background: </strong>There is substantial evidence linking migraines to gastrointestinal (GI) issues. Conditions such as irritable bowel syndrome and colitis often co-occur with migraines and GI symptoms are common among migraine patients. However, the evidence supporting the efficacy of gut microbiome-targeted therapies for managing migraines is limited. This systematic review aimed to describe the existing evidence of the gut microbiome in patients with migraine compared to healthy individuals. Additionally, it sought to examine how therapies targeting the gut microbiome including prebiotics, probiotics and synbiotics, might influence clinical outcomes.</p><p><strong>Methods: </strong>We performed searches on Embase, PubMed, and the Cochrane Library to identify studies in migraines and the gut microbiome, focusing on those which investigated the gut microbiome composition and gut microbiome-targeted therapies. Key data was extracted and analysed including study details, patient demographics, migraine type, comorbidities, and clinical outcomes. For gut microbiome composition studies, bacterial diversity and abundance was noted. For gut microbiome-targeted therapies studies, treatment types, dosages, and patient outcomes was recorded.</p><p><strong>Results: </strong>A significant difference between various genera of microbes was reported between migraine patients and controls in several studies. Bacteroidetes (also named Bacteroidota), proteobacteria, and firmicutes (also named Bacillota) phyla groups were found significantly abundant in migraine, while studies were conflicted in the abundance of Actinobacteria and Clostridia with regards to increased migraine risk in migraine patients. Patients with migraine had a gut microbiome with reduced species number and relative abundance, as well as a distinct bacterial composition compared to controls. Synbiotic and synbiotic/probiotic combination treatments have been shown in five randomised controlled trials and one open label pilot study to significantly decrease migraine severity, frequency, duration and painkiller consumption.</p><p><strong>Conclusions: </strong>The significant alterations in microbial phyla observed in migraine patients suggest a potential microbial signature that may be associated with migraine risk or chronic progression. However, the mechanistic underpinnings of these associations remain unclear. This systemic review found that probiotic and synbiotic/probiotic combination therapies may be promising interventions for migraine management, offering significant reductions in migraine frequency and painkiller use. Future randomised controlled studies are needed to evaluate the optimal length of treatment and impact on patient related quality of life.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":"26 1","pages":"125"},"PeriodicalIF":7.3,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12096802/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144119839","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reliability and validity of the Arabic version of cluster headache impact questionnaire in both active episodic and chronic cluster headache.","authors":"Mona Hussein, Mona Af Nada, Amr Hassan, Mohamed Abdelghaffar, Mona Ali, Alaa Elmazny, Rehab Magdy","doi":"10.1186/s10194-025-01991-8","DOIUrl":"10.1186/s10194-025-01991-8","url":null,"abstract":"<p><strong>Background: </strong>Clinical evaluation of cluster headache (CH) impact on patients' quality of life is crucial in research and clinical practice. To our knowledge, none of the measures that evaluated CH-related disability were validated in Arabic. This study aimed to evaluate the reliability and validity of the Arabic version of Cluster Headache Impact Questionnaire (CHIQ) in both active episodic CH (eCH) and chronic CH (cCH).</p><p><strong>Methods: </strong>Patients with active eCH or cCH were requested to answer the Arabic version of CHIQ, Depression, anxiety and stress scale- 12 (DASS-12), and Short form-12 health survey (SF-12). Cronbach's α and intraclass correlation coefficient (ICC) were used to assess the test reliability. Convergent validity and Explanatory factor analysis of CHIQ items were also assessed.</p><p><strong>Results: </strong>Seventy-two patients with active eCH and another 16 with cCH were evaluated. Patients with cCH had a significantly higher median value of CHIQ total score in comparison to those with eCH (P-value < 0.001). No ceiling or floor effects were detected in CHIQ total score. The Arabic version of CHIQ showed excellent reliability (Cronbach's α = 0.901). The intraclass correlation coefficient of CHIQ total score was 0.983 indicating excellent test re-test reliability. The CHIQ scores were significantly correlated with scores of DASS-12 (r = 0.477) and SF-12 (r=-0.691), supporting the convergent validity of the scale. Exploratory factor analysis revealed two factors labelled as \"physical and cognitive impact\" and \"psychological impact\" factors.</p><p><strong>Conclusion: </strong>Arabic version CHIQ is a reliable and valid tool for measuring CH-related disability and quality of life in patients with eCH and cCH.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":"26 1","pages":"126"},"PeriodicalIF":7.3,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12096683/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144119838","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Induction of more severe central sensitization in a medication overuse headache model mice through active ingestion of rizatriptan.","authors":"Zhenjie Ma, Chenhao Li, Wenhao Bai, Wei Xie, Mingjie Zhang, Han Xiao, Cancan Chen, Yang Li, Wenwen Zhang, Deqi Zhai, Yingyuan Liu, Dengfa Zhao, Wenjing Tang, Zhao Dong, Ruozhuo Liu, Shengyuan Yu","doi":"10.1186/s10194-025-02066-4","DOIUrl":"10.1186/s10194-025-02066-4","url":null,"abstract":"<p><strong>Background: </strong>Medication overuse headache (MOH) is a secondary headache disorder arising from excessive use of acute analgesics in patients with primary headache. Current animal models that predominantly employ passive drug administration fail to recapitulate the hallmark feature of voluntary medication-seeking behaviour observed clinically. Therefore, we established a novel MOH mouse model with the active ingestion of rizatriptan (RIZ) to better simulate the clinical characteristics of MOH and explore changes in brain activation patterns.</p><p><strong>Methods: </strong>C57BL/6 J mice received intraperitoneal injections of nitroglycerin (NTG, 10 mg/kg) every other day. During the feeding period, they were provided with two bottles-one containing an RIZ solution (0.02 mg/kg) and the other containing deuterium depleted water (DDW)-allowing for voluntary intake. The bottle containing the RIZ solution was marked with a fixed colour indicator at the nozzle. Behavioural assessments included mechanical allodynia (von Frey filaments), anxiety-like behaviours (elevated plus maze, EPM and open field test, OFT), and drug-seeking quantification. Quantitative data from c-Fos immunostaining across 25 specific brain regions were subjected to Z score normalization, followed by three-tiered computational analyses: 1) hierarchical clustering (complete linkage) to characterize activation patterns, 2) Pearson correlation analysis for functional connectivity mapping, and 3) graph-theoretical network analysis (Cytoscape 3.2.1) to identify hub regions and their topological relationships. The small molecule calcitonin gene-related peptide (CGRP) receptor antagonist, rimegepant (100 mg/kg, i.p., 7 injections) was administered during the modelling period, and withdrawal of RIZ and NTG was applied after modelling to observe behavioural and histological changes.</p><p><strong>Results: </strong>Chronic RIZ consumption exacerbated NTG-induced cutaneous allodynia, prolonged central sensitization, and increased anxiety-like behaviour. Rimegepant attenuated allodynia progression, whereas withdrawal of RIZ and NTG normalized pain thresholds. Network analysis identified the prelimbic cortex (PrL) and spinal trigeminal nucleus caudalis (SPVC) as hub nodes. The PrL exhibited extensive functional connectivity with addiction-related regions (the insular cortex, IC and nucleus accumbens), whereas the SPVC showed predominant connections with pain-processing areas.</p><p><strong>Conclusion: </strong>This study pioneers an ethologically valid MOH model that reflects more severe central sensitization and recapitulates active medication-seeking behaviour. PrL-mediated addiction-like-behaviour pathways and SPVC-centred nociceptive processing may play roles in the development of MOH. These findings provide novel neuromodulation targets (PrL, IC, SPVC) for refractory MOH management.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":"26 1","pages":"123"},"PeriodicalIF":7.3,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12090462/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144109888","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic influence of the brain imaging phenotypes, brain and cerebrospinal fluid metabolites and brain genes on migraine subtypes: a Mendelian randomization and multi-omics study.","authors":"Ping-An Zhang, Jie-Lin Wang, Mei-Hua Dong, Xiang-Chun Huang, Nai-Jian Li, Run-Dong Qin, Jing Li","doi":"10.1186/s10194-025-02063-7","DOIUrl":"10.1186/s10194-025-02063-7","url":null,"abstract":"<p><strong>Background: </strong>Migraine is a complex neurological disorder with high prevalence but unclear pathogenesis. Numerous studies have suggested that migraine is associated with alterations in brain imaging phenotypes (BIPs) and dysregulation of cerebrospinal fluid (CSF) and brain metabolism; however, causal evidence remains limited. Mendelian randomization (MR) offers a powerful approach for inferring causality using genetic instruments.</p><p><strong>Methods: </strong>Firstly, we conducted linkage disequilibrium score regression (LDSC) to evaluate genetic correlations between migraine, including the migraine with aura (MA) and migraine without aura (MO) subtypes, and BIPs, CSF, and brain metabolites. Traits that showed genetic correlations with migraine, MA, or MO were retained for subsequent MR analysis with the corresponding migraine phenotype. Traits showing significant correlations were analyzed using bidirectional two-sample MR (TSMR), followed by two-step TSMR to identify cross-omics mediation effects. Additionally, We also applied summary-data-based MR (SMR) to detect brain-region-specific genes with potential causal effects. Enrichment analyses (KEGG, GO, PPI, transcription factor, and miRNA networks) were conducted to further explore underlying mechanisms.</p><p><strong>Results: </strong>LDSC identified significant genetic correlations with 73 BIPs and 40 metabolites for overall migraine, 71 BIPs and 37 metabolites for MA, and 49 BIPs and 62 metabolites for MO. Enrichment analysis revealed that genetically associated metabolites were predominantly involved in amino acid metabolic pathways. TSMR identified 6 BIPs and 2 metabolites causally linked to overall migraine, 3 BIPs and 3 metabolites to MA, and 2 BIPs and 5 metabolites to MO. Most migraine-related BIPs mapped to the parietal lobe. Reverse MR analysis showed that overall migraine causally influenced 4 BIPs and 3 metabolites, while MA and MO affected 1 BIP and 1 metabolite, and 3 BIPs and 1 metabolite, respectively. Mediation analysis revealed five significant mediation pathways were identified. SMR analysis identified FAM83B and CIB2 consistently showing inhibitory effects across most regions. Enrichment analysis showed that these genes were predominantly involved in immune activation and cell adhesion.</p><p><strong>Conclusions: </strong>Our study integrates cross-omics analyses to investigate the causal links between brain structure, metabolic alterations, gene expression, and migraine including its MA and MO subtypes. These findings provide novel insights into the pathophysiological mechanisms and potential targets for intervention across migraine subtypes.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":"26 1","pages":"124"},"PeriodicalIF":7.3,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12090607/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144110925","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dysfunctional mesocorticolimbic circuitry in cluster headache.","authors":"Stefania Ferraro, Greta Demichelis, Jean Paul Medina Carrion, Dan Liu, Benjamin Becker, Michael Maes, Davide Fedeli, Giuseppe Ciullo, Susanna Usai, Marina Grisoli, Luisa Chiapparini, Alberto Cecchini Proietti, Luca Giani, Anna Nigri, Massimo Leone","doi":"10.1186/s10194-025-02017-z","DOIUrl":"10.1186/s10194-025-02017-z","url":null,"abstract":"<p><strong>Background: </strong>This study aimed to identify mesocorticolimbic functional abnormalities in cluster headache (CH) patients, disentangling the roles of chronification and affective symptoms.</p><p><strong>Methods: </strong>Using the monetary incentive delay fMRI task to directly engage these pathways, we investigated functional alterations in key regions of this network in chronic (n = 23) and episodic CH patients (n = 49) compared to a control group (n = 32). After processing the fMRI data, we extracted beta values from selected regions and for contrasts of interest and entered them into logistic regression models adjusted for potential confounders (such as depressive and anxiety symptoms and smoking habit) to test their association with the diagnoses (chronic CH and control subjects, episodic CH and control subjects).</p><p><strong>Results: </strong>Results showed that chronic CH patients exhibited reduced ventral tegmental area (VTA) activity and a tendency towards significance (p = 0.056) for an increased medial prefrontal cortex (mPFC) responsiveness during reward anticipation, alongside a significant decrease in mPFC activity during reward outcomes. Episodic patients displayed abnormal mPFC activity across both reward phases, but coupled with intact VTA responses. Importantly, these functional abnormalities were not correlated to depressive and anxiety symptoms and smoking habits.</p><p><strong>Conclusions: </strong>These findings suggest that chronic CH patients experience an imbalance in the VTA-mPFC pathway, while episodic patients may show early signs of this emerging dysfunction. Moreover, the observed reward processing alterations seem distinct from those associated with affective disorders, possibly highlighting unique mechanisms underlying the pathophysiology of CH.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":"26 1","pages":"121"},"PeriodicalIF":7.3,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12090487/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144110922","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}