Journal of Headache and Pain最新文献

{"title":"From bench to bedside: relevant animal models across the migraine attack phases.","authors":"Georgii Krivoshein, Mignon van der Watt, Teresa Jordà-Baleri, Katrin Põld, Viktor Gkotzamanis, Arn M J M van den Maagdenberg, Eloisa Rubio-Beltran, Philip R Holland","doi":"10.1186/s10194-026-02369-0","DOIUrl":"10.1186/s10194-026-02369-0","url":null,"abstract":"<p><p>Migraine is a debilitating brain disorder for which there remains a considerable therapeutic gap that needs to be addressed in order to develop novel effective treatment options for patients. Preclinical translational models have contributed significantly to migraine research by improving our understanding of migraine pathophysiology as well as identifying and validating new drug targets. In this review, we will summarise key animal models and discuss how commonly used experimental readouts used in these models can be integrated for the investigation of the various phases of a migraine attack. A major focus is to highlight the translational potential of the experimental models and how they can help bridge the gap between preclinical research and clinical application and how increased understanding of fundamental disease mechanisms can form the basis of improved migraine treatments. Providing such a resource may inform the broader migraine research community on which model and readout they might consider when studying a specific phase of the migraine attack, when evaluating the efficacy of new possible drugs and innovative therapeutic strategies.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":"27 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13202895/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148031722","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":"Long-range circuit of the mouse spinal trigeminal nucleus caudalis.","authors":"Leili Tang, Tao Jiang, Anan Li, Yong Deng, Xiangning Li, Hui Gong, Miao Ren","doi":"10.1186/s10194-026-02380-5","DOIUrl":"10.1186/s10194-026-02380-5","url":null,"abstract":"<p><strong>Background: </strong>The spinal trigeminal nucleus caudalis (SPVC) is a key central relay in the trigeminal circuit that processes orofacial nociceptive and somatosensory information. However, its long-range connectivity patterns remain poorly characterized.</p><p><strong>Methods: </strong>Using viral tracing and fluorescence micro-optical sectioning tomography (fMOST), we obtained three-dimensional datasets of long-range input-output circuits of the SPVC in adult male C57BL/6J mice. An orofacial pain model was established by injecting formalin into the whisker pad of adult male C57BL/6J mice, followed by pain behavior assays and cfos immunohistochemical staining. Using adult male Fos-CreER mice combined with viral tracing and fMOST imaging, we mapped the projection patterns of pain-activated neurons in the SPVC.</p><p><strong>Results: </strong>We systematically mapped the long-range connectivity patterns of SPVC in adult male mice. High-resolution, three-dimensional whole-head imaging with the fMOST system revealed substantial neuronal input to the SPVC from the trigeminal ganglion (TG) neurons innervating the facial skin and vomeronasal glands. Cortical input neurons exhibited clear subregional preferences. Whole-brain and spinal cord continuous imaging further demonstrated that the SPVC projects centrally via two distinct circuits that target the thalamus and the parabrachial nucleus (PB), respectively. The thalamic projections were further subdivided into dorsal and ventral circuits and exhibited clear subregional specificity within the thalamus. Additionally, the SPVC extended to the spinal cord through three major projection circuits, reaching as far as the lumbar segments. Along the whole-brain and spinal projection circuits, synaptic connections were identified in major target regions, including the submedial nucleus of the thalamus (SMT), ventral posteromedial nucleus of the thalamus (VPM), PB, and the C1 segment of the cervical spinal cord. Furthermore, tracing of SPVC pain-activated neurons revealed that they do not project to cerebellar crus 2 of the ansiform lobule (ANcr2) and paraflocculus (PFL).</p><p><strong>Conclusions: </strong>High-resolution 3D imaging reveals the SPVC long-range connectome across head, brain, and spinal cord. Together, these findings establish a comprehensive connectivity framework for understanding the neural mechanisms underlying orofacial pain and provide a foundation for advances in basic sensory research and disease prevention and treatment.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":" ","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13390467/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148015973","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":"Kappa opioid receptor availability correlates with depressive symptom burden in chronic migraine: a preliminary investigation.","authors":"Dajung J Kim, Majid Saberi, Tanpreet Kaur, Xia Shao, Robert A Koeppe, Peter J H Scott, Frank Porreca, Alexandre F DaSilva","doi":"10.1186/s10194-026-02398-9","DOIUrl":"10.1186/s10194-026-02398-9","url":null,"abstract":"<p><strong>Background: </strong>Chronic pain is frequently accompanied by affective disturbances, yet the neurobiological mechanisms linking pain perception and affective vulnerability remain poorly understood. The kappa opioid receptor (KOR)/dynorphin system has emerged as a key modulator of nociceptive and affective processes, in part through regulation of dopamine signaling within mesocorticolimbic circuits. However, the role of KOR signaling to pain-related affect and functional integration in migraine has not been characterized.</p><p><strong>Methods: </strong>We measured KOR availability using positron emission tomography (PET) with [¹¹C]LY2795050, a selective KOR antagonist radioligand in 12 individuals with chronic migraine (CM; 11 F/1 M; 42.0 ± 15.1 years) and 11 healthy controls (HC; 9 F/2 M; 40.9 ± 17.0 years). PET scans included an early resting and late sustained thermal pain stimulus stress (STPTS) phase, with KOR availability quantified as non-displaceable binding potential (BP_ND). Group differences in KOR BP_ND were assessed using region-of-interest (ROI) and voxel-wise analyses focusing on corticolimbic regions. Resting-state functional MRI (rs-fMRI) was additionally acquired to explore ROI-to-ROI functional connectivity (rsFC) within predefined regions. Exploratory interaction analyses examined whether group moderated the relationship between KOR BP_ND and rsFC strength. Associations between KOR BP_ND and clinical measures of pain intensity and affective symptoms were assessed using Spearman's rho correlation.</p><p><strong>Results: </strong>Compared with HC, individuals with CM showed significantly elevated KOR BP_ND in the left anterior insula and lateral orbitofrontal cortex, particularly during STPTS phase. Exploratory interaction analyses revealed a differential relationship between fronto-insular KOR BP_ND and rsFC between the anterior and posterior insula. In addition, higher fronto-insular KOR BP_ND was positively correlated with greater subclinical depressive symptom scores, which were predominantly in the minimal-to-mild range, in the CM group.</p><p><strong>Conclusions: </strong>These findings indicate altered fronto-insular KOR availability in individuals with CM and suggest that KOR signaling may contribute to affective symptom burden, even at subclinical levels. The observed associations between KOR availability and rs-fMRI measures warrant cautious interpretation and further investigation in larger samples.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":" ","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13397754/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148015910","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":"Over 600 million people aged 18-65 will have headache tomorrow: global 1-day prevalence and recall bias from a meta-analysis of individual participant data (N = 38,512) from the general populations of 15 countries.","authors":"Andreas Kattem Husøy, Shengyuan Yu, Ruozhuo Liu, Akbar A Herekar, Bilal Ahmed, Arif D Herekar, Callixte Kuate Tegueu, Anastase Dzudie Tamdja, Annick Mélanie Magnerou, Najib Kissani, Latifa Adarmouch, Thierry Adoukonou, Mendinatou Agbetou, Oyéné Kossi, Mehila Zebenigus, Redda Tekle-Haimanot, Dawit K Worku, Girish N Rao, Girish B Kulkarni, Gopalkrishna Gururaj, Mohammed Al Jumah, Ali M Al Khathaami, Suliman Kojan, Guiovanna Quispe, Carlos Palomino-Diaz, Youssoufa Maiga, Robert P Cowan, Mattias Linde, Ajay Risal, Debashish Chowdhury, Krishnan Anand, Ashish Duggal, Otgonbayar Luvsannorov, Dorjkhand Baldorj, Selenge Enkhtuya, Ilya Ayzenberg, Zaza Katsarava, Gretchen L Birbeck, Daiva Rastenytė, Lars Jacob Stovner, Timothy J Steiner","doi":"10.1186/s10194-026-02359-2","DOIUrl":"10.1186/s10194-026-02359-2","url":null,"abstract":"<p><strong>Background: </strong>Our recent estimate of the global 1-year prevalence of headache among those aged 18-65 years was 65%: considerably higher than previous estimates, but based solely on high-quality epidemiological data derived from a large population-based sample. Here we present complementary estimates of 1-day prevalence.</p><p><strong>Methods: </strong>We performed a meta-analysis of individual participant data from cross-sectional surveys among population-representative samples (age range 18-65 years) from 15 countries and all world regions. All used the Headache-Attributed Restriction, Disability, Social Handicap and Impaired Participation (HARDSHIP) questionnaire, including the question \"did you have a headache yesterday?\", from which 1-day prevalence was determined. An algorithmic process applying modified ICHD criteria yielded separate estimates for migraine, tension-type headache (TTH) and probable medication-overuse headache (pMOH: the association of headache on ≥ 15 days/month and medication overuse). We analysed associations with age, gender and country-income level, and adjusted prevalence estimates for these factors. We calculated predicted 1-day prevalence from 1-year prevalence and reported headache frequency.</p><p><strong>Results: </strong>Among the 38,512 participants, females (53.4%) and participants from low- (17.1%) or lower-middle-income countries (64.6%) were overrepresented, but age distribution fairly matched that of the world. Overall, 13.7% (95% CI: 13.3-14.0) reported headache yesterday, females (17.1% [16.6-17.6]) more than males (9.7% [9.3-10.2]). Migraine was the most common headache type yesterday (6.0% [5.8-6.3]), followed by TTH (4.1% [3.9-4.3]) and pMOH (2.3% [2.2-2.5]). One-day headache prevalence was higher in low/lower-middle-income countries (13.9% [13.6-14.3]) than in high/upper-middle-income countries (12.4% [11.6-13.2]). Predicted 1-day prevalence (10.9% [10.7-11.1]) was considerably lower than observed 1-day prevalence (13.7% [13.3-14.0]), although not among those with pMOH (3.1% [3.0-3.3] versus 2.3% [2.2-2.5]). Adjusted for age, gender and country-income level, global 1-day prevalence estimates were 13.1% (12.8-13.5) for any headache, 5.7% (5.5-5.9) for migraine, 3.9% (3.7-4.1) for TTH and 2.4% (2.3-2.6) for pMOH, with 1.0% undiagnosed.</p><p><strong>Conclusion: </strong>Assuming yesterday was no different from any other day, an estimated 13.1% (N = 641,900,000) of the world's population aged 18-65 years will have headache tomorrow; almost half will be migraine. People with migraine or TTH underestimate the frequency of headache episodes. Since headache-attributed burden is usually estimated from recalled frequency over 1-12 months, this also may be underestimated.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":" ","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13217788/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148015887","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":"Shared genetic architecture between depression and migraine: a large-scale genome-wide cross-trait analysis.","authors":"Min Zhang, Qiyin Li, Yuan Zhao, Yadong Peng, Jiangyou Yu, Cheng Gan, Liwei Tang, Keyi Liu, Ying Liu, Zheng Zhang, Xinglian Wang, Mingshuang Tang, Chenggang Jiang, Dongqing Gu","doi":"10.1186/s10194-026-02402-2","DOIUrl":"10.1186/s10194-026-02402-2","url":null,"abstract":"<p><strong>Background: </strong>Depression and migraine are highly prevalent neuropsychiatric disorders that frequently co-occur. However, the extent to which they share genetic determinants, particularly for postpartum depression (PPD), an underexplored subtype, remains insufficiently understood.</p><p><strong>Methods: </strong>We performed a large-scale genome-wide cross-trait analysis using summary statistics for depression phenotypes (overall depression, major depressive disorder [MDD], PPD) and migraine subtypes (migraine, migraine with aura [MA], migraine without aura [MO]). Genetic correlations were estimated using linkage disequilibrium score regression (LDSC) and GNOVA. Pleiotropically associated loci were identified through cross-trait meta-analysis, followed by fine-mapping and colocalization analyses to prioritize potential loci with stronger evidence for shared causal signals. Functional annotation and gene-based analyses were conducted to explore biological relevance. Bidirectional and multivariable Mendelian randomization (MVMR) were applied to assess potential causal relationships.</p><p><strong>Results: </strong>We observed significant global and local genetic correlations between depression and migraine (LDSC r_g=0.289, P = 3.36 × 10^- 33; GNOVA r_g=0.266, P = 1.32 × 10^- 47), with consistent findings across MDD, PPD, and migraine subtypes. Cross-trait meta-analysis identified 39 genome-wide pleiotropically associated loci, of which two (rs11877758 and rs138709872) showed strong evidence of colocalization (PPH4 > 0.8). Functional annotation demonstrated enrichment in brain regulatory elements and neural pathways. MR analysis provided evidence consistent with a potential causal effect of genetically predicted depression liability on the risk of migraine (odds ratio [OR] = 1.439, P = 6.09 × 10^- 20) and MO (OR = 1.502, P = 4.73 × 10^- 5), whereas reverse-direction associations were also observed but were smaller in magnitude (OR = 1.037, P = 2.56 × 10^- 4). In MVMR, the depression-to-migraine associations remained consistent after adjustment (OR range: 1.405-1.585), while migraine-to-depression associations were attenuated. PPD showed significant genetic correlation with migraine but limited evidence for a potential causal relationship.</p><p><strong>Conclusions: </strong>Depression and migraine show substantial genetic overlap and exhibit an asymmetric pattern of potential causal relationships, with stronger MR evidence for the depression-to-migraine direction than for the reverse direction. The pleiotropically associated loci provide genomic evidence for future mechanistic and translational investigation across depression and migraine subtypes. The findings also highlight PPD as a genetically related but potentially distinct subtype warranting further investigation.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":" ","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13390404/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148015937","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":"Pharmacological mechanisms underlying neurovascular alterations related to resistant and refractory migraine: CGRP pathways and beyond.","authors":"Damiana Scuteri, Michalis Kodounis, Masahito Katsuki, Burcu Bezgal, Natalia Bednarczyk, Savvas Konstantinos Alevetsovitis, Justyna Wołos, Mariana Henriques, Teresa Ascensão Pinheiro, Antoinette MaassenVanDenBrink, Christian Lampl","doi":"10.1186/s10194-026-02395-y","DOIUrl":"10.1186/s10194-026-02395-y","url":null,"abstract":"<p><strong>Background: </strong>Migraine is the fourth leading cause of disability worldwide. It impairs patients' physical, emotional and social functioning, as well as their productivity. This is also due to poor pharmacological control of attacks in difficult-to-treat patients. Despite several therapeutic strategies available, including the game-changing calcitonin gene-related peptide (CGRP)-targeted small-molecule and biotechnological drugs, 40% of patients remain resistant or even refractory. The aim of this review is to highlight the neurovascular mechanisms underlying poor response or nonresponse to antimigraine drugs, with particular focus on the phenomena related to the CGRP pathway.</p><p><strong>Methods: </strong>Eligibility criteria, search strategy and information sources were established a priori: PubMed, Scopus, Cochrane Library, Web of Science and ScienceDirect were searched for studies published from database inception to the date of the last search on July 05th, 2025.</p><p><strong>Results: </strong>Non-response to antimigraine treatment is closely linked to clinical and neurobiological factors that increase the overall disease burden. Underlying these challenges are mechanisms involving genetic and epigenetic modifications that contribute to inter-individual variability in pharmacokinetics and pharmacodynamics. Additionally, CGRP as well as other neuropeptides, implicated in the neurovascular basis of migraine, may play a significant role. Targeting these mechanisms may help overcome treatment resistance and refractoriness, as defined by the European Headache Federation. Combination therapies, including the latest available treatments, might represent a promising strategy. Thus, they deserve further investigation to confirm efficacy without worsening the safety profile.</p><p><strong>Conclusions: </strong>A deeper understanding of the neurovascular pharmacology and pathophysiology of migraine is essential to pave the way for more personalized and effective treatments. tudies are needed to clarify the neuropharmacological, genetic, and epigenetic mechanisms that underlie resistance and refractoriness to pharmacological therapies, affecting the CGRP pathway both directly and indirectly.</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":"2026-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13234986/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147987796","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":"A modified FLIT-B model of trigeminal neuralgia reveals anterior cingulate cortex involvement in anxiety-like behavior in mice.","authors":"Xiaoqin Lian, Taoxia Xie, Chen Chen, Jing Deng, Sijing Zhao, Tongtong Gao, Mei Fu, Weiyi Ye, Kunxin Yang, Na Zhou, Lei Tang, Dihan Lu, Xia Feng, Shiqian Shen, Qian Chen","doi":"10.1186/s10194-026-02394-z","DOIUrl":"10.1186/s10194-026-02394-z","url":null,"abstract":"<p><strong>Background: </strong>Trigeminal neuralgia (TN) is a debilitating orofacial pain disorder characterized by paroxysmal, lancinating pain and prominent affective comorbidities. Increasing evidence suggests that chronic TN involves abnormal plasticity in supraspinal pain circuits. However, the lack of animal models that faithfully recapitulate key clinical features of TN has limited mechanistic investigations of these central processes. Here, building upon our previously established foramen lacerum impingement of the trigeminal nerve root (FLIT) model, we developed an improved glass bead-based version (FLIT-B) that enables reproducible and controlled compression of the trigeminal nerve root and facilitates investigation of supraspinal mechanisms in TN.</p><p><strong>Methods: </strong>In the FLIT-B model, calibrated glass beads were implanted through the foramen lacerum to compress the trigeminal nerve root. Behavioral assays were used to assess sensory and affective phenotypes, while histological analyses evaluated trigeminal nerve pathology. To examine supraspinal circuit alterations, neuronal activation in the primary somatosensory barrel field (S1BF), anterior cingulate cortex (ACC), amygdala, and hippocampus was assessed using c-Fos immunostaining. Structural and functional changes in excitatory neurons, particularly in the ACC, were further analyzed using AAV-mediated labeling, in vivo fiber photometry, and two-photon calcium imaging in both sham and FLIT-B mice.</p><p><strong>Results: </strong>FLIT-B mice exhibited spontaneous pain-like behaviors, including asymmetric facial grimacing and peri-orbital hair loss associated with excessive grooming, suggesting persistent orofacial discomfort. Histological analyses confirmed consistent trigeminal nerve root demyelination. c-Fos staining and calcium imaging revealed widespread activation of the S1BF, ACC, amygdala, and hippocampus, with the ACC showing the highest degree of activation, particularly in spontaneous activity patterns. Morphological analyses demonstrated significant dendritic remodeling in excitatory neurons of the ACC and S1BF. Chemogenetic inhibition of ACC excitatory neurons significantly alleviated both pain-like and anxiety-like behaviors.</p><p><strong>Conclusions: </strong>The FLIT-B model provides a reproducible and clinically relevant rodent model of TN by compression of the trigeminal nerve root at an anatomically relevant site. Using this model, we identify ACC-centered structural and functional plasticity as a key supraspinal substrate linking chronic trigeminal pain to affective disturbances.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":" ","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13371341/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148005344","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":"Pharmacological and transcutaneous auricular vagal targeting of endoplasmic reticulum stress in the trigeminal ganglion alleviates migraine-like behaviors.","authors":"Huan-Jun Lu, Meng-Xuan Huang, Yi-Fan Wang, Ning-Yi Ren, Chun-Yu Dong, Meng-Lu Liu, Xin-Yi Huang, Yong-Jing Gao, Hao Wu","doi":"10.1186/s10194-026-02400-4","DOIUrl":"10.1186/s10194-026-02400-4","url":null,"abstract":"<p><strong>Background: </strong>Endoplasmic reticulum (ER) stress has emerged as a key player in the development of diverse chronic pain disorders; however, its specific contribution to migraine pathophysiology has yet to be fully elucidated. Although accumulating evidence indicates that transcutaneous auricular vagus nerve stimulation (taVNS) mitigates chronic pain, the precise molecular mechanisms governing this effect remain poorly understood. This study investigates the functional contribution of ER stress and its downstream signaling mechanisms in a nitroglycerin (NTG)-induced mouse model of chronic migraine, and whether taVNS exerts analgesic effects by modulating ER stress within trigeminal ganglion (TG) neurons.</p><p><strong>Methods: </strong>Chronic migraine was induced in mice via repeated intraperitoneal injection of NTG. Facial mechanical hypersensitivity was assessed using Von Frey filaments. Light-aversive and anxiety-like behaviors were evaluated through open field testing and light/dark box testing. mRNA and protein expression were analyzed using quantitative PCR (qPCR) and Western blot, respectively. The cellular localization of alpha7 nicotinic acetylcholine receptor (α7nAChR) receptors in the TG was determined by immunofluorescence staining. TG neuronal excitability was recorded using whole-cell patch-clamp electrophysiology. taVNS was delivered via the auricular branch of the vagus nerve using varying parameters.</p><p><strong>Results: </strong>NTG injection induced migraine-like behaviors characterized by increased facial mechanical allodynia, anxiety-like behaviors and photophobia. Significant activation of ER stress-related marker proteins was observed in the TG of NTG-treated mice, and intra-TG injection of the ER stress inhibitor tauroursodeoxycholic acid (TUDCA) alleviated migraine-like behaviors and reduced neuronal excitability of TG neurons. Transcriptomic sequencing revealed that TUDCA treatment reduced the expression of genes related to the PI3K-AKT signaling pathway and cytokine-cytokine receptor interaction. Western blot confirmed that phosphorylated AKT (p-AKT) expression was also reduced by TUDCA. qPCR showed that NTG-induced upregulation of inflammatory mediators (including Ccl6, Ccl8, Ccl11 and Il-16) was also decreased by TUDCA. Additionally, daily treatment with 20 Hz taVNS mitigated ER stress, neuronal hyperexcitability, and inflammatory mediators' production, which were reversed by an inhibitor of α7nAChR.</p><p><strong>Conclusions: </strong>ER stress serves as an upstream driver of neuronal hypersensitivity and neuroinflammation in the TG, leading to pain sensitization, while taVNS targets this core organellar stress state through α7nAChR activation to exert therapeutic effects. These findings provide a novel mechanistic perspective and identify potential therapeutic targets for migraine treatment.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":" ","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13390144/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148005334","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":"Clinical, demographic, and lifestyle characteristics of patients with cervicogenic headache: comparison with an age- and sex-matched group of individuals with migraine.","authors":"Magdalena Nowaczewska, Sara Kierońska-Siwak, Marcin Straburzyński, Marta Waliszewska-Prosół, Anna Gryglas-Dworak","doi":"10.1186/s10194-026-02401-3","DOIUrl":"10.1186/s10194-026-02401-3","url":null,"abstract":"<p><strong>Background: </strong>Cervicogenic headache (CEH) can be frequently misdiagnosed as migraine. This study aimed to compare clinical, demographic, and lifestyle characteristics of patients with CEH and individuals with migraine.</p><p><strong>Methods: </strong>The retrospective cross-sectional study included 112 patients with CEH and 112 age- and sex-matched individuals with migraine consulted at a single headache center in 2022-2026. The analysis involved clinical and demographic characteristics, and lifestyle factors, among them dominant sleep posture.</p><p><strong>Results: </strong>Compared with individuals with migraine, patients with CEH were diagnosed with headache at an older age (36.27±11.95 vs. 22.62±11.13 years, p < 0.001), had shorter duration of disease (4.08±5.40 vs. 17.74±11.60 years, p < 0.001), more often reported neck pain, also occurring independently of headache (76.92% vs. 39.56%, p < 0.001), more frequently presented with greater occipital nerve (GON) sensitivity to palpation (85.44% vs. 30.21%, p < 0.001) and vitamin B12 deficiency (56.86% vs. 9.38%, p < 0.001). The CEH group contained a larger proportion of active smokers (43.75% vs. 10.71%, p < 0.001) and belly (prone) sleepers (40.18% vs. 14.29%, p < 0.001) than the migraine group. A multivariate regression analysis identified belly sleeping (OR = 11.10, p = 0.006), smoking (OR = 22.61, p = 0.005), and vitamin B12 deficiency (OR = 8.58, p = 0.005) as independent determinants of CEH.</p><p><strong>Conclusions: </strong>CEH differs from migraine in terms of selected clinical, demographic, and lifestyle characteristics. Neck pain independent of headache, GON sensitivity to palpation, older age at the onset of headache, and shorter time elapsed from the first manifestation to referral might be diagnostic prompts in suspected CEH. Belly sleeping, vitamin B12 deficiency, and smoking appear as independent determinants of CEH and might be considered in the prevention and management of this condition.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":" ","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13292324/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147987789","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":"Functional characterisation of dura mater αCGRP degradation fragments at vascular, immune, and CGRP receptor targets.","authors":"Mette N Jensen, Jens B Kristensen, Maria Castrillo, Philip V Reducha, Karin M L Nordahl, Debbie L Hay, Kristian A Haanes","doi":"10.1186/s10194-026-02390-3","DOIUrl":"10.1186/s10194-026-02390-3","url":null,"abstract":"<p><strong>Objective: </strong>Calcitonin gene related peptide (CGRP) is a central mediator in migraine and can trigger attacks in susceptible individuals. Therapies targeting CGRP or its receptor provide clinical benefit, but treatment responses vary. This suggests that local factors regulating CGRP availability and signalling within migraine relevant tissues may influence its biological effects. The extent and functional relevance of CGRP degradation at the dura mater, including possible effects on biomarker detection, remain insufficiently characterised.</p><p><strong>Methods: </strong>Proteomic analyses were used to identify human αCGRP (hαCGRP) degradation fragments generated in rat meningeal preparations. Functional properties of full-length hαCGRP and selected degradation fragments were assessed at the dura mater, in isolated arteries, in mast cell degranulation assays, and at CGRP receptors in vitro. Fragment interactions with a CGRP ELISA were examined to assess potential interference with detection of full-length CGRP. Male Sprague Dawley rats were used for the ex vivo experiments.</p><p><strong>Results: </strong>hαCGRP disappeared rapidly in the meningeal environment and reduced transdural resistance in the dura mater. Seven predominant degradation fragments accounted for ~ 81.5% of the detected fragment pool. None of the fragments showed agonist activity at the CGRP receptor or altered dural resistance or mast cell degranulation. In vascular assays, the fragments were likewise inactive, with the exception of the C-terminal fragment hαCGRP_11-37, which displayed weak competitive antagonism at the CGRP receptor. This was confirmed at both the human and rat CGRP receptor in vitro. Although the identified fragments were not directly detected by the CGRP ELISA, selected fragments interfered with intact hαCGRP measurements, indicating that degradation products can influence biomarker readout.</p><p><strong>Conclusion: </strong>Local degradation of hαCGRP at the dura mater primarily generates fragments without measurable vascular, immune, or receptor activating effects. The main consequence of this processing appears to be reduced hαCGRP bioavailability rather than formation of secondary bioactive signalling peptides. At the same time, fragment dependent interference in ELISA based detection indicates that local hαCGRP metabolism may affect interpretation of CGRP biomarker measurements in migraine relevant tissues.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":"27 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13196087/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147987814","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}