Journal of Headache and Pain最新文献

{"title":"Tear fluid Calcitonin gene-related peptide in patients with idiopathic intracranial hypertension headache - a prospective case-control study.","authors":"Cem Thunstedt, Ad Shehi, Ozan E Eren, Andreas Straube, Katharina Kamm, Ruth Ruscheweyh","doi":"10.1186/s10194-026-02453-5","DOIUrl":"10.1186/s10194-026-02453-5","url":null,"abstract":"<p><strong>Background: </strong>Headache is the most common symptom of idiopathic intracranial hypertension (IIH) and may persist despite therapy, with a significant impact on quality of life. Since calcitonin gene-related peptide (CGRP) plays a crucial role in the pathophysiology and management of primary headaches such as migraine, this raises the question whether CGRP also contributes to headache in IIH. Therefore, we compared tear fluid CGRP levels between IIH patients with headache and healthy controls, and in IIH patients before and after CSF pressure normalization by therapeutic lumbar puncture.</p><p><strong>Methods: </strong>IIH patients with headache attributed to IIH and healthy controls were included. To avoid confounding with chronic migraine, IIH patients with a chronic migraine phenotype were excluded. Tear fluid was collected from IIH patients and controls. In IIH patients, an additional measurement was performed approximately 3 h after therapeutic lumbar puncture. CGRP levels were analyzed using a commercially available ELISA.</p><p><strong>Results: </strong>Twenty-three IIH patients (all female; age: 34.0 ± 8.8 years) and 20 healthy controls (all female, age: 25.7 ± 5.5 years) were included. IIH patients had 16.4 ± 12.3 headache days per month and headache was mostly bilateral and pressing. Baseline tear fluid CGRP levels were significantly lower in IIH patients compared to healthy controls (2.4 ± 1.2 ng/ml vs. 4.9 ± 4.2 ng/ml, p < 0.001). There was no significant change in CGRP levels in IIH patients before vs. after therapeutic lumbar puncture (2.4 ± 1.2 vs. 2.4 ± 1.7 ng/ml, p = 0.236). Similarly, in the subgroup with immediate headache improvement, CGRP levels remained unchanged (before: 2.2 ± 0.9 ng/ml, after: 2.8 ± 2.4 ng/ml; p = 0.674).</p><p><strong>Conclusions: </strong>Tear fluid CGRP levels were lower in IIH patients with headache but without a chronic migraine phenotype compared to healthy controls. In addition, CSF pressure normalization was not associated with changes in CGRP levels after 3 h. These results do not support a major role of CGRP in IIH-associated headache without a chronic migraine phenotype.</p><p><strong>Trial registration: </strong>The study was previously registered at the German Clinical Trial Register (DRKS www.drks.de) (DRKS00025278), Trial registration date 25.06.2021.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":"27 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13397755/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148578656","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":"Interictal burden in migraine: a systematic review of conceptual domains and measurement properties of instruments.","authors":"Cornelius Angerhöfer, Yutaro Fuse, Samuel Van Langenhove, Thomas Canning, Alice C von Alvensleben, Sheharyar Ahmad, Ane Murillo, Laia Boada, Maria M Roque, Antoinette MaassenVanDenBrink, Christian Lampl","doi":"10.1186/s10194-026-02458-0","DOIUrl":"10.1186/s10194-026-02458-0","url":null,"abstract":"<p><strong>Background: </strong>Migraine imposes significant burden not only during acute attacks but also during headache-free interictal periods. Several patient-reported outcome measures (PROMs) have been used to assess this interictal burden, yet the quality of their measurement properties has not been systematically evaluated.</p><p><strong>Objectives: </strong>To identify instruments used to assess interictal burden in migraine, evaluate their measurement properties using the COSMIN methodology, and synthesize the conceptual domains of interictal burden.</p><p><strong>Methods: </strong>A systematic search of MEDLINE, Embase, PsycINFO, CINAHL, and Web of Science Core Collection was conducted from database inception to 20 February 2026. Studies evaluating measurement properties of PROMs assessing interictal burden or migraine impact in migraine populations were eligible. The COSMIN risk-of-bias checklist and criteria for good measurement properties were applied. Findings were synthesized in accordance with PRISMA 2020.</p><p><strong>Results: </strong>Among 29 included studies, three instruments were identified: the Migraine Interictal Burden Scale-4 (MIBS-4; 26 studies), the Eurolight questionnaire (1 study), and the Fear of Attacks Inventory (FAMI; 2 studies). Seven conceptual domains of interictal burden were identified: functional impairment, social and relational impact, psychological and emotional distress, cognitive dysfunction, sensory symptoms, physical symptoms, and behavioral modifications. Evidence of measurement properties was concentrated in construct validity (19 studies) and responsiveness (8 studies). Structural validity, internal consistency, test-retest reliability and content validity were sparsely evaluated. The MIBS-4 demonstrated consistent convergent and known-groups validity and sensitivity to change across preventive therapies, including CGRP-targeted treatments and onabotulinumtoxinA.</p><p><strong>Conclusions: </strong>The MIBS-4 is the most widely used instrument for assessing interictal burden. Despite encouraging evidence of construct validity and responsiveness, comprehensive psychometric studies addressing content and structural validity, reliability, and measurement error, alongside conceptual work towards broader interictal burden assessment, are needed.</p><p><strong>Registration: </strong>PROSPERO CRD420261296323; Clinical trial number: not applicable.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":"27 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13401311/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148584514","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":"Neck musculoskeletal dysfunction in patients with chronic primary headaches.","authors":"Ignacio Elizagaray-García, Celia María de-Toro-Cañizares, Javier Díaz-de-Terán, Alfonso Gil-Martínez, Kerstin Luedtke","doi":"10.1186/s10194-026-02413-z","DOIUrl":"10.1186/s10194-026-02413-z","url":null,"abstract":"<p><strong>Objective: </strong>To compare cervical musculoskeletal findings in chronic forms of migraine, tension-type headache, cluster headache, and healthy controls and identify which variables were most strongly associated with headache frequency, neck disability and impact in each headache group.</p><p><strong>Methods: </strong>Single-blinded cross-sectional study with a non-probabilistic sample. A blinded physiotherapist assessed 129 participants: chronic migraine (n = 35), chronic tension-type headache (n = 30), chronic cluster headache (n = 34) and headache-free controls (n = 30). Psychosocial and cervical musculoskeletal variables (head posture, total cervical active range of motion, flexion-rotation test, motor control, symptom reproduction and resolution) were compared. Backward linear regression analyses were performed to explore associations between cervical variables and headache frequency. neck disability and headache-related impact.</p><p><strong>Results: </strong>Compared to controls, chronic cluster headache showed reduced total cervical active range of motion [F(3,128) = 8.8; p = 0.001, d = 0.75], retraction [F(3,128) = 4.66; p = 0.007, d = 0.70], protraction [F(3,128) = 7.77; p = 0.017, d = 0.73] and flexion-rotation [F(3,128) = 3.68; p = 0.014, d = 0.72]. While sex confounded total active range of motion (p = 0.009); neither variable influenced protraction or retraction (all p ≥ 0.26). Familiar head pain was evoked more in chronic migraine (68.6%) and tension-type headache (72.4%) than controls (23.3%) [χ²(1) = 20.85; p = 0.008; χ²(1) = 29.99; p = 0.0003]. Erector spinae activity was negatively associated with cluster headache frequency (Adjusted R²=0.25; β=-0.65; p = 0.02), cervical retraction was negatively associated with migraine frequency (Adjusted R²=0.11; β=-1.58; p = 0.03), and no significant associations were found for tension-type headache.</p><p><strong>Conclusion: </strong>This study provides the first comprehensive assessment of cervical musculoskeletal function in chronic cluster headache and directly compares it with the main chronic primary headaches and free-headache control group. Chronic cluster headache showed reduced cervical range of motion and impaired flexion-rotation versus controls; Although some differences between headache groups were observed, cervical musculoskeletal impairments were broadly present across chronic headache populations, without a clearly distinctive disorder-specific pattern. Neck musculoskeletal findings were not associated with headache frequency or impact.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":"27 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13570541/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148955922","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":"Targeting neuronal FKBP5 attenuates mechanical allodynia by suppressing NF-κB-mediated neuroinflammation in an NTG-induced chronic migraine mouse model.","authors":"Cheng Peng, Tianhua Fan, Gang Zhou, Min Zhao, Tianxiao Wang, Tingting Cao, Jingyuan Zheng, Zijuan Guo, Guining Liang, Zhenchang Zhang, Ji-Song Guan, Yonggang Wang","doi":"10.1186/s10194-026-02460-6","DOIUrl":"10.1186/s10194-026-02460-6","url":null,"abstract":"<p><strong>Background: </strong>Chronic migraine (CM) is a debilitating neurological disorder characterized by persistent trigeminovascular sensitization and neuroinflammation. While FK506-binding protein 51 (FKBP5) modulates spinal neuroinflammation in chronic pain, its specific role in trigeminovascular nociceptive processing and CM pathogenesis remains largely unknown.</p><p><strong>Methods: </strong>We used a nitroglycerin (NTG)-induced CM mouse model. Following RNA-sequencing (RNA-seq) of total RNA isolated from trigeminal nucleus caudalis (TNC) tissue lysates, target expression was validated via reverse transcription quantitative PCR (RT-qPCR), Western blotting, and immunofluorescence. To establish causality, we used a neuron-specific CRISPR-Cas9 editing system for Fkbp5 knockout within the TNC, alongside pharmacological interventions using the specific FKBP5 antagonist SAFit2 and the nuclear factor kappa B (NF-κB) inhibitor PDTC. Migraine-like behaviors were evaluated using von Frey filaments, coupled with biochemical analyses of NF-κB cascade activation and trigeminovascular neuroinflammation.</p><p><strong>Results: </strong>RNA-seq, RT-qPCR, Western blotting, and immunofluorescence consistently confirmed a marked upregulation of Fkbp5 mRNA and FKBP5 protein in the TNC of NTG-treated mice, predominantly localized to neurons. Concurrently, significant microglial and astrocytic activation was observed in the TNC. Both neuron-specific Fkbp5 knockout and pharmacological inhibition with SAFit2 significantly attenuated NTG-induced periorbital and hind paw mechanical allodynia. Furthermore, FKBP5 deficiency blunted the NTG-triggered phosphorylation of p65 and IκBα, effectively suppressing the downstream release of pro-inflammatory cytokines, including interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), as well as the upregulation of calcitonin gene-related peptide (CGRP) and c-Fos. Crucially, targeted blockade of the NF-κB cascade with PDTC recapitulated the protective behavioral and biochemical effects of FKBP5 deficiency.</p><p><strong>Conclusions: </strong>We demonstrate that neuronal FKBP5 is significantly associated with CM pathogenesis. FKBP5 sustains mechanical allodynia by activating the NF-κB-mediated neuroinflammatory cascade. Consequently, targeting FKBP5 represents a promising therapeutic strategy for CM.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":"27 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149228017","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":"Genetic regulation of cell type-specific chromatin accessibility contributes to migraine etiology.","authors":"Qiuhan Xu, Zhaohui Chai, Yuning Zhang, Jian Shen","doi":"10.1186/s10194-026-02450-8","DOIUrl":"10.1186/s10194-026-02450-8","url":null,"abstract":"<p><strong>Background: </strong>Migraine is a common and disabling neurological disorder, yet most causal regulatory variants and their target cell types remain unresolved. Disease-associated variants are enriched in non-coding cis-regulatory elements, indicating that they act by modulating gene regulation. Chromatin accessibility quantitative trait loci (caQTLs) capture genetic effects on these regulatory elements with cell-type resolution and can pinpoint the regulatory regions and cellular contexts mediating disease risk. However, brain cell type-specific caQTLs have not previously been integrated with migraine genetics.</p><p><strong>Methods: </strong>We performed two-sample Mendelian randomization (MR) using brain cell type-specific cis-caQTLs from sorted neuronal (NeuN⁺) and non-neuronal (NeuN⁻) nuclei of 616 postmortem brain donors as exposures, with FinnGen Release 12 migraine GWAS (26,894 cases / 374,605 controls) as the discovery outcome. Open chromatin regions (OCRs) reaching Bonferroni-corrected significance were replicated in the UK Biobank (25,393 cases / 433,047 controls) and the Million Veteran Program (31,836 cases / 405,831 controls), and further evaluated by Bayesian colocalization and instrument-level phenome-wide screening. Multi-modal target gene annotation integrated Hi-C, cis-eQTL, ABC, and ENCODE-rE2G models; nominated genes were further evaluated for drug-target safety using gene-level rare-variant collapsing analyses and characterized for regional brain expression using the Human Protein Atlas.</p><p><strong>Results: </strong>Of 15,334 OCR-migraine causal estimates, 19 reached Bonferroni-corrected significance in FinnGen R12. Seven were Bonferroni-replicated in both replication cohorts with concordant directions, and three showed strong colocalization (PP.H4 > 0.80). After excluding one OCR with extensive cardiovascular pleiotropy, two non-neuronal OCRs were retained: Peak_7234 (chr1:115,282,554-115,283,246) and Peak_124742 (chr4:35,524,861-35,526,079). Multi-modal annotation of Peak_7234 convergently nominated NGF as the highest-priority candidate target gene, with TSPAN2 as a secondary candidate; Peak_124742 lies in a gene-poor region with insufficient regulatory annotation to confidently nominate a target gene. Neither NGF nor TSPAN2 showed associations reaching phenome-wide significance.</p><p><strong>Conclusions: </strong>Two non-neuronal brain open chromatin regions are prioritized as likely causal contributors to migraine risk. At the chr1:115.3 Mb region, NGF is nominated as the highest-priority candidate downstream target, with TSPAN2 as a complementary candidate. These findings extend cell type-specific causal mapping of migraine to the regulatory layer and identify candidate regulatory elements and target genes for further mechanistic and translational investigation.</p><p><strong>Clinical trial number: </strong>Not applicable.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":" ","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148549584","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":"Normative structural MRI deviation factors summarize patient-level neuroanatomical heterogeneity across episodic and chronic migraine.","authors":"Chenyu Dai, Mengqian Ye, Xinhao Li, Zhewei Yan, Lechao Ye, YangJingJie Mao, Huimin Wang, Yan Li, Keyang Chen, Xiaozheng Liu, Beilei Hu, Yungang Cao, Fangwang Fu","doi":"10.1186/s10194-026-02464-2","DOIUrl":"10.1186/s10194-026-02464-2","url":null,"abstract":"<p><strong>Background: </strong>Structural MRI findings in migraine are inconsistent across cohorts, suggesting that group contrasts may obscure patient-level heterogeneity. We tested whether individualized normative structural deviations could be summarized into interpretable patient-level factor-weight dimensions related to chronicity and clinical burden.</p><p><strong>Methods: </strong>In this single-center cross-sectional study, 249 adults with ICHD-3 migraine (198 episodic, 51 chronic) and 57 local healthy controls underwent 3.0-T MRI. Released PCNtoolkit lifespan models were locally adapted with controls to estimate patient-level deviation z scores for 158 FreeSurfer features. Non-negative matrix factorization was applied to the absolute-deviation matrix; directional negative- and positive-deviation models were sensitivity analyses. Covariate-adjusted associations were FDR-corrected within prespecified families.</p><p><strong>Result: </strong>The primary model identified two stable factor-weight dimensions. Factor 1 captured a subcortical-limbic-brainstem/global-volume deviation pattern and was associated with chronic migraine (OR per 1-SD, 1.50; q = 0.036), MIDAS (beta = 16.46; q = 0.007), and monthly headache days (beta = 9.41; q < 0.001). Factor 2 mainly reflected cortical-thickness deviations, showed a borderline inverse association with chronic migraine (OR = 0.68; q = 0.054), and was associated with high absolute-deviation burden (OR = 2.37; q < 0.001). HIT-6 showed no corrected factor-specific association. Removing cranial-size-sensitive features preserved factor structure and main Factor 1 associations.</p><p><strong>Conclusion: </strong>Normative structural MRI deviations in migraine can be summarized into non-mutually exclusive deviation-burden factors with patient-level weights. Factor 1 showed the most consistent associations with chronic migraine, headache frequency, and MIDAS; these associations attenuated in restricted sensitivity analyses, and external validation is required before clinical application.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":" ","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148549579","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":"Abstracts from the 19th European Headache Congress (EHC).","authors":"","doi":"10.1186/s10194-026-02378-z","DOIUrl":"10.1186/s10194-026-02378-z","url":null,"abstract":"","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":"27 Suppl 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13383177/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148520231","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":"Exploratory development of prediction models for pharmacotherapy outcomes in trigeminal neuralgia: a combined analysis based on multi-source data.","authors":"Hongan Yang, Baijintao Sun, Mingtao Li, Xuezhao Yang, Mingyan Li, Chuan Zhang, Hanfeng Yang","doi":"10.1186/s10194-026-02463-3","DOIUrl":"10.1186/s10194-026-02463-3","url":null,"abstract":"<p><strong>Background: </strong>Drug-refractory trigeminal neuralgia (DRTN) represents a formidable challenge in clinical management, with approximately 30%-50% of patients eventually progressing to DRTN. Early identification of high-risk DRTN populations and prediction of the timing of pharmacotherapy failure are crucial for optimizing clinical treatment strategies.</p><p><strong>Methods: </strong>This retrospective study enrolled 163 primary trigeminal neuralgia patients receiving carbamazepine/oxcarbazepine with comprehensive imaging. A partially-blinded approach was used for data extraction: 135 patients (December 2022-December 2024) formed the primary cohort and 28 patients (December 2021-December 2022) served as the temporally separated validation cohort. Data comprised clinical baseline characteristics, pain and emotional scale scores, and imaging parameters. A nested cross-validation framework (20 random seeds) was used for model development, with feature selection confined to the training cohort within each seed. Five machine learning models were compared via pooled ROC curves aggregated across seeds, and SHAP analysis interpreted the optimal model at the median-performing seed. Age-unadjusted and age-adjusted multivariate Cox regression models were constructed, with four parallel univariate screening thresholds evaluated in sensitivity analyses. Model performance was assessed by Kaplan-Meier analysis, time-dependent ROC curves, and the concordance index.</p><p><strong>Results: </strong>The support vector machine with radial basis function kernel (SVM-RBF) achieved the optimal performance, with average AUCs of 0.927 ± 0.041, 0.824 ± 0.049, and 0.806 ± 0.058 in the training, test, and validation cohort, respectively. In a sensitivity analysis using four univariate Cox screening thresholds, with age at first pain onset forced into all multivariate models, pain involved extent and medial temporal lobe atrophy (MTA) score were both identified as significant, independent candidate prognostic markers. Both Cox models showed moderate discriminative capacity for short-to-medium-term DRTN prognosis but attenuated long-term predictive efficacy.</p><p><strong>Conclusion: </strong>The SVM-RBF model, integrating multi-source heterogeneous data, demonstrated promising predictive performance for DRTN onset risk across the present cohort. The Cox models showed moderate discriminative capacity for short-to-medium-term prognosis, though long-term predictive accuracy was attenuated. These findings provide preliminary evidence for early risk stratification and individualized treatment of DRTN, while underscoring the need for improved survival prediction strategies to address the limited long-term performance of the current Cox models.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":" ","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13670614/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148497617","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":"IRAK-M attenuates pain hypersensitivity and anxiety-like behaviors in a nitroglycerin-induced chronic migraine mouse model with concomitant reductions in microglial activation and neuroinflammation.","authors":"Xiao-Tao Liang, Shi-Ru Xie, Xi-Mao Liu, Xiao-Yu Zhu, Yi-Fan Xiong, Yu Hong, Zhi-Yong Wu, Yu-Heng Zou, Yun-Yan Zhao, Yue-Wen Ding, Xiao-Shan Liang, Wei Xie","doi":"10.1186/s10194-026-02457-1","DOIUrl":"10.1186/s10194-026-02457-1","url":null,"abstract":"<p><strong>Background: </strong>Chronic migraine (CM) is a disabling neurological disorder in which neuroinflammatory mechanisms and central sensitization are thought to contribute to disease pathophysiology. Interleukin-1 receptor-associated kinase M (IRAK-M), which is predominantly expressed in microglia in the central nervous system (CNS), is an endogenous negative regulator of innate immune signaling. Previous studies have linked IRAK-M to the restraint of Toll-like receptor 4 (TLR4) signaling and NLR family pyrin domain-containing 3 (NLRP3) inflammasome-related responses. However, the role of IRAK-M in CM-related pathophysiology and associated neuropsychiatric comorbidities remains unclear. This study aimed to investigate the function of IRAK-M and its underlying molecular mechanisms in a mouse model of chronic migraine.</p><p><strong>Methods: </strong>Mice were repeatedly given intraperitoneal injections of nitroglycerin (NTG; 10 mg/kg) to create a chronic migraine model. Mechanical and thermal sensitivity were assessed using von Frey filaments and the hot-plate test, respectively; light aversion and anxiety-like behaviors were evaluated using the light-aversion test, open-field test, and elevated plus-maze test. To further clarify the role of IRAK-M, both transgenic genetic engineering approaches and adeno-associated virus (AAV)-mediated expression strategies were employed. The underlying molecular mechanisms were further investigated using quantitative PCR, immunoblotting, immunofluorescence, and three-dimensional reconstruction.</p><p><strong>Results: </strong>Repeated administration of NTG increased IRAK-M protein in the trigeminal nucleus caudalis (TNC). IRAK-M deficiency exacerbated mechanical and thermal hyperalgesia, increased c-Fos and CGRP expression, and enhanced microglial activation; these changes were accompanied by increased TLR4/NF-κB-related signaling, NLRP3 inflammasome activation, and GSDMD cleavage. Conversely, TNC-targeted IRAK-M overexpression attenuated pain hypersensitivity and anxiety-like behavioral alterations and was accompanied by corresponding reductions in neuroinflammatory molecular and cellular readouts. These findings support IRAK-M as an important regulator of central sensitization and neuroinflammatory responses in a chronic migraine model.</p><p><strong>Conclusions: </strong>Our findings identify IRAK-M as an important preclinical regulator of microglial reactivity and neuroinflammatory responses in the NTG-induced chronic migraine model. IRAK-M manipulation was accompanied by bidirectional changes in TLR4/NF-κB- and NLRP3/GSDMD-related signaling, pain hypersensitivity, and anxiety-like behavioral alterations. These findings provide a preclinical rationale for further investigation of IRAK-M-related neuroimmune signaling in migraine.</p><p><strong>Clinical trial number: </strong>Not applicable.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":" ","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13670728/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148471139","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":"From tooth pain to trigeminal sensitization: translational models, experimental readouts, and mechanism-guided therapeutic opportunities in odontogenic and headache-related orofacial pain.","authors":"Ezgi Cansu Firinciogullari, Kiran Alluri, Hanjun Wang, Sumit Yadav","doi":"10.1186/s10194-026-02452-6","DOIUrl":"10.1186/s10194-026-02452-6","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Odontogenic pain is one of the most intense forms of orofacial pain, yet durable mechanism-directed therapies remain limited. Traditionally, tooth pain has been framed as a local consequence of pulpal, dentinal, periodontal, or periapical disease. However, contemporary orofacial pain and headache frameworks increasingly position dental pain within a broader trigeminal pain network, where nociceptive input from the teeth and surrounding tissues may contribute to referred facial pain, headache-related orofacial pain overlap, and trigeminal sensitization. In this review, we synthesize odontogenic pain as a clinically accessible model for studying peripheral-to-central trigeminal pain mechanisms. To align the review questions, scope, and content, the review is structured around five linked domains: clinically relevant phenotypes, peripheral-to-central mechanisms, phenotype-matched models and readouts, biomarker-based target engagement, and mechanism-guided therapeutic and trial-design strategies. We emphasize the hot tooth phenotype, most commonly associated with symptomatic irreversible pulpitis, as a translational state in which severe peripheral inflammation, tissue acidosis, ion-channel remodeling, local anesthetic difficulty, neuroimmune activation, and central amplification converge. We summarize key molecular and circuit-level mechanisms, including inflammatory mediator release, ion-channel and receptor pathways related to thermal, acid, purinergic, sodium, calcium, mechanosensitive, and G protein-coupled signaling, trigeminal ganglion plasticity, satellite glial activation, calcitonin gene-related peptide signaling, trigeminocervical convergence, and central sensitization. We also discuss how preclinical models and experimental readouts can be aligned with specific clinical phenotypes, including five clinical phenotype domains: dentin hypersensitivity; acute pulpitis; the hot tooth phenotype as the index severe inflammatory pulpitis state; persistent dentoalveolar or post-procedural pain, including post-traumatic trigeminal neuropathic pain; and headache-related orofacial pain overlap. By linking clinical phenotypes, mechanistic models, experimental readouts, biomarkers, target engagement, therapeutic strategies, and trial-design considerations, this framework may help bridge the gap between preclinical pain research and clinical application. Reframing odontogenic pain as a biologically informative trigeminal pain state may support the development of biomarker-guided, mechanism-informed, and more durable analgesic strategies for refractory dental and headache-related orofacial pain. Importantly, persistent or refractory odontogenic and headache-related orofacial pain is shaped not only by peripheral and central neurobiological mechanisms but also by patient-level contextual contributors such as sleep disruption, stress, prior pain and treatment experience, and affective-motivational processing, which help explain why patients with compa","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":" ","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13670828/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148471164","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}