Journal of Headache and Pain最新文献

{"title":"Lateral habenula-rostromedial tegmental nucleus circuit mediates inflammatory pain in mice.","authors":"Yanfei Sun, Jing Cao, Chunpeng Xu, Jiangtao Sun, Xiaofeng Liu, Zhenguang Shi, SiMeng An, Danyang Zhao, Dongjie Sun, Xuxin Wang, Guoyan Zhao, Chi Zhang, Guangjian Li, Jinyu Xiao, Jing Yang, Hua Zhao","doi":"10.1186/s10194-025-02052-w","DOIUrl":"https://doi.org/10.1186/s10194-025-02052-w","url":null,"abstract":"<p><strong>Background: </strong>The monoamine system, particularly the serotonergic neurons in the dorsal raphe nucleus (DRN), associated with the synthesis and release of 5-hydroxytryptamine, is crucial for regulating pain. The lateral habenula (LHb) modulates DRN neurons by acting through GABAergic neurons located in the rostromedial tegmental nucleus (RMTg). However, the role of RMTg in mediating the LHb and regulating pain remains unclear. Thus, we aimed to assess the role of the LHb-RMTg pathway in inflammatory pain.</p><p><strong>Methods: </strong>Male C57BL/6 mice were used in the chemogenetic experiments, while male and female Vglut2-ires-cre mice were used in the optogenetic experiments; in both experiments, inflammatory pain model and control groups were established. We performed the Hargreaves and Von Frey tests to assess nociceptive behavior as well as immunohistochemistry staining after chemogenetic activation experiments. Statistical analyses were performed using a t-test, one-way analysis of variance (normally distributed data) or Kruskal-Wallis test (non-normally distributed data) and two-way analysis of variance.</p><p><strong>Results: </strong>Chemogenetic activation/inhibition of RMTg-projecting LHb excitatory neurons was sufficient to decrease or increase heat sensitivity thresholds. Additionally, inhibition of the LHb-RMTg circuit reversed the decreased heat sensitivity thresholds under inflammatory pain conditions using chemogenetic and optogenetic approaches. However, this circuit did not affect mechanical allodynia thresholds, and chemogenetic activation of the circuit decreased c-Fos immunoreactivity in the DRN.</p><p><strong>Conclusions: </strong>Our results indicate that activating glutamatergic neurons within the LHb heightens pain sensitivity by triggering GABAergic neurons in the RMTg, which in turn influences neuronal activity in the DRN. This research offers fresh perspectives on the pain mechanism, potentially revealing new therapeutic avenues for managing inflammatory pain.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":"26 1","pages":"105"},"PeriodicalIF":7.3,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12057000/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143975295","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":"The burden of migraine and predictions in the Asia-Pacific region, 1990-2021: a comparative analysis of China, South Korea, Japan, and Australia.","authors":"Yun-Xia Wang, Guang-Shuang Lu, Jin-Jing Zhao, Wei Dai, Na Zheng, Guo-En Yao, Ruo-Zhuo Liu","doi":"10.1186/s10194-025-02048-6","DOIUrl":"https://doi.org/10.1186/s10194-025-02048-6","url":null,"abstract":"<p><strong>Background: </strong>Migraine is a leading cause of disability worldwide, significantly impacting quality of life and healthcare systems. Despite its high prevalence and burden, migraine remains underprioritized in global health policies. This study examines the epidemiological trends of migraine in Australia, China, Japan, and South Korea from 1990 to 2021, highlighting regional disparities and forecasting future burdens.</p><p><strong>Methods: </strong>This study utilized data from the Global Burden of Disease (GBD) 2021 to analyze incidence, prevalence, and years lived with disability (YLDs) of migraine. Age-standardized rates (ASRs) were calculated to enable fair cross-country comparisons. Joinpoint regression analysis was applied to assess temporal trends, while Bayesian age-period-cohort (BAPC) modeling was used to project future trends until 2050. Additionally, decomposition analysis was conducted to differentiate the effects of population aging, growth, and epidemiological changes.</p><p><strong>Results: </strong>In 2021, China had the highest migraine burden, with 13.05 million new cases and 184.75 million prevalent cases, followed by Australia, Japan, and South Korea. Incidence rates peaked in adolescence (10-14 years), while prevalence and disability were highest in middle-aged women (40-44 years). From 1990 to 2021, Australia exhibited stable trends, China experienced increasing burden, Japan saw a decline due to aging, and Korea exhibited mixed patterns influenced by opposing demographic and epidemiological forces. Future projections suggest a stable trend in Australia, declining incidence in China and Japan, and continued burden in Korea.</p><p><strong>Conclusion: </strong>Migraine remains a significant public health challenge across all four countries, with age, gender, and demographic changes playing key roles in burden variations. The study highlights the need for region-specific healthcare strategies and age- and gender-sensitive interventions. Future research should explore socioeconomic, behavioral, and healthcare access factors to refine migraine management strategies.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":"26 1","pages":"104"},"PeriodicalIF":7.3,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12057080/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144020929","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":"Who is the patient with resistant myofascial temporomandibular disorders pain? A somatosensory, psychosocial, and genetic characterization.","authors":"Giancarlo De la Torre Canales, Rodrigo Lorenzi Poluha, Flávia Fonseca Carvalho Soares, Dyna Mara Araújo Oliveira Ferreira, Alfonso Sánchez-Ayala, Leonardo Rigoldi Bonjardim, Malin Ernberg, Paulo César Rodrigues Conti","doi":"10.1186/s10194-025-02055-7","DOIUrl":"https://doi.org/10.1186/s10194-025-02055-7","url":null,"abstract":"<p><strong>Background: </strong>Resistance to treatments have been assessed in chronic conditions such as migraine, but not in temporomandibular disorders (TMD). This study aimed to identify factors that influence treatment outcome in patients with myofascial TMD pain.</p><p><strong>Methods: </strong>Seventy-two females were divided into three groups: TMD successfully treated (TMD-S, n = 24), TMD resistant to treatment (TMD-R, n = 24) and Controls without TMD (n = 24). Criteria for resistance included: less than 30% pain reduction after three months of conservative treatment and an average pain intensity > 50 mm (VAS) during the last month. Quantitative sensory testing (QST), psychosocial status and genetic polymorphisms were examined. ANOVA on ranks (psychosocial variables) with Dunn's test as post-hoc or ANOVA (age and somatosensory variables) with Tukey test as post-hoc test, and Dwass-Steel-Critchlow-Fligner test (genetic variables) were used for univariate groups comparisons. Multivariate statistics were used to identify outcomes that separated the groups.</p><p><strong>Results: </strong>QST assessment revealed lower baseline pressure pain threshold and higher wind-up ratio in the trigeminally and spinally innervated areas in the TMD-R group compared with the other groups (p = 0.01). Also, the TMD-R group presented higher values in all assessed psychosocial variables (p < 0.01) and higher prevalence of the HTR1A polymorphism rs6295 (p = 0.02) compared with the other groups at baseline. Multivariate analysis showed that the three variables that distinguished the best between TMD-R and TMD-S were sleeping quality, central sensitization, and depressive symptoms.</p><p><strong>Conclusion: </strong>Psychosocial, somatosensory, and genetic alterations are related to unsuccessful treatment response in myofascial TMD patients.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":"26 1","pages":"98"},"PeriodicalIF":7.3,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12054165/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143983709","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":"Unveiling new insights into migraine risk stratification using machine learning models of adjustable risk factors.","authors":"Yu-Chen Liu, Ye-Hai Liu, Hai-Feng Pan, Wei Wang","doi":"10.1186/s10194-025-02049-5","DOIUrl":"https://doi.org/10.1186/s10194-025-02049-5","url":null,"abstract":"<p><strong>Background: </strong>Migraine ranks as the second-leading cause of global neurological disability, affecting approximately 1.1 billion individuals worldwide with severe quality-of-life impairments. Although adjustable risk factors-including environmental exposures, sleep disturbances, and dietary patterns-are increasingly implicated in pathogenesis of migraine, their causal roles remain insufficiently characterized, and the integration of multimodal evidence lags behind epidemiological needs.</p><p><strong>Methods: </strong>We developed a three-step analytical framework combining causal inference, predictive modeling, and burden projection to systematically evaluate modifiable factors associated with migraine. First, two-sample mendelian randomization (MR) assessed causality between five domains (metabolic profiles, body composition, cardiovascular markers, behavioral traits, and psychological states) and the risk of migraine. Second, we trained ensemble machine learning (ML) algorithms that incorporated these factors, with Shapley Additive exPlanations (SHAP) value analysis quantifying predictor importance. Finally, spatiotemporal burden mapping synthesized global incidence, prevalence, and disability-adjusted life years (DALYs) data to project region-specific risk and burden trajectories through 2050.</p><p><strong>Results: </strong>MR analyses identified significant causal associations between multiple adjustable factors (including overweight, obesity class 2, type 2 diabetes [T2DM], hip circumference [HC], body mass index [BMI], myocardial infarction, and feeling miserable) and the risk of migraine (P < 0.05, FDR-q < 0.05). The Random Forest (RF)-based model achieved excellent discrimination (Area under receiver operating characteristic curve [AUROC] = 0.927), identifying gender, age, HC, waist circumference [WC], BMI, and systolic blood pressure [SBP] as the predictors. Burden mapping projected a global decline in migraine incidence by 2050, yet persistently high prevalence and DALYs burdens underscored the urgency of timely interventions to maximize health gains.</p><p><strong>Conclusions: </strong>Integrating causal inference, predictive modeling, and burden projection, this study establishes hierarchical evidence for adjustable migraine determinants and translates findings into scalable prevention frameworks. These findings bridge the gap between biological mechanisms, clinical practice, and public health policy, providing a tripartite framework that harmonizes causal inference, individualized risk prediction, and global burden mapping for migraine prevention.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":"26 1","pages":"103"},"PeriodicalIF":7.3,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12057085/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143975301","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":"Inhibition of S100A4 decreases neurotoxic astrocyte reactivity and attenuates neuropathic pain via the TLR4/NF-κB pathway in a rat model of spinal nerve ligation.","authors":"Tao Xue, Yu Song, Jie Zhao, Guiyong Fan, Zhiyuan Liu","doi":"10.1186/s10194-025-02045-9","DOIUrl":"https://doi.org/10.1186/s10194-025-02045-9","url":null,"abstract":"<p><p>S100A4 participates in inflammation and immune reactions in the central nervous system and is involved in the pathogenesis of multiple neurological disorders. It can affect the functions of astrocytes, microglia, infiltrating cells and neurons and further modulates neuronal plasticity and survival in the central nervous system. However, its impact on astrocyte phenotypes and neuropathic pain and the intrinsic mechanisms involved remain poorly understood. Here, we showed that S100A4 was markedly upregulated after spinal nerve ligation and was mainly expressed in neurons in the spinal dorsal horn. Transcriptional inhibition of S100A4 with niclosamide attenuated neuropathic pain after surgery. We found that astrocytes differentiated into C3-positive reactive populations, so-called neurotoxic (A1) astrocytes and identified differentially expressed genes and specific molecular expression signatures after ligation. Neurotoxic astrocyte reactivity is regulated by exogenous S100A4 in vitro, and targeted inhibition of S100A4 suppresses neurotoxic astrocyte proliferation in rats. Finally, we reported that TLR4/NF-κB signaling pathway is a downstream of S100A4 activation, and that specific depletion this pathway suppresses deleterious A1 astrocyte activation and further attenuates the development and maintenance of neuropathic pain after spinal nerve ligation. Thus, S100A4 in neurons plays a key role in neurotoxic astrocyte reactivity and can be targeted for treatment to prevent and alleviate neuropathic pain.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":"26 1","pages":"97"},"PeriodicalIF":7.3,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12044810/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144014131","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":"Tolerability of repetitive dihydroergotamine infusions paired with an adjustment in preventive treatment strategy in chronic headache disorders in children and youth.","authors":"Sara Pavitt, Cynthia Morris, Lauren Shin, Andrew Jones, Beata Vayngortin, Natalia Zorrilla, Chengshi Jin, Isabel Allen, Amy A Gelfand","doi":"10.1186/s10194-025-02035-x","DOIUrl":"https://doi.org/10.1186/s10194-025-02035-x","url":null,"abstract":"<p><strong>Background: </strong>In adults, intravenous (IV) dihydroergotamine (DHE) has been shown to be effective at improving medium term outcomes in patients with chronic headache disorders. The IV formulation is utilized given its superior bioavailability. We aim to assess the safety and effectiveness of repetitive IV DHE infusions paired with an adjustment of a preventive treatment strategy within children and youth with chronic headache disorders.</p><p><strong>Methods: </strong>A retrospective chart review was conducted of children and youth diagnosed with a chronic headache disorder who were admitted for DHE from January 2014 - October 2020. Patients completed a 5-day, standardized protocol. A new preventive was started one week after discharge. Data were collected from pre- and post-admission clinic notes. Safety and tolerability were assessed. Results were evaluated using descriptive statistics and compared with paired t-tests.</p><p><strong>Results: </strong>One hundred and eighty-seven patients were included for review. Sixty-eight percent (127) had chronic migraine (CM), 20% (37) new daily persistent headache (NDPH) and 12% (23) persistent headache attributed to head trauma (PHHT). The median (range) age was 16 years (7-21), and median (range) number of previous preventive trials was 4 (0-21). At follow-up, patients with CM had a significant decrease in headache days per month from 28.6 to 26.3 days (95% CI -4.1 to -1.3) p < 0.001, baseline headache intensity decreased from 5.9/10 to 5.3/10 (95% CI -1.3 to -0.1) p = 0.006, number of severe headache days per month decreased from 11.5 to 7.9 days (95% CI -6.5 to -2.3), p < 0.001, and monthly days of acute medication use from 12.1 to 9.8 days (95% CI -4.5 to -0.7) p = 0.002. In patients with NDPH there were significant decreases in baseline headache intensity from 6.4/10 to 5.3/10 (95% CI -1.7 to -0.3) p = 0.005 and monthly days of acute medication usage from 9.2 days to 5.9 days (95% CI -7.8 to -0.1) p = 0.043. Patients with PHHT had a significant decrease in headache days per month from 29 to 24 days (95% CI -9.4 to -0.7) p = 0.031. The most common side effects were nausea (85%) and mild leg cramping (60%).</p><p><strong>Conclusion: </strong>Repetitive DHE infusions followed by preventive treatment adjustment was well tolerated and significantly reduced headache frequency, baseline intensity, number of severe days and/or acute medication usage in children and youth with refractory headache disorders.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":"26 1","pages":"93"},"PeriodicalIF":7.3,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12042534/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143996244","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":"Correction: Uncovering drug targets for cluster headache through proteome-wide Mendelian randomization analysis.","authors":"Zhonghua Xiong, Zhi Guo, Lei Zhao, Dong Qiu, Yanliang Mei, Xiaoshuang Li, Peng Zhang, Mantian Zhang, Geyu Liu, Tianshuang Gao, Yonggang Wang, Xueying Yu","doi":"10.1186/s10194-025-02032-0","DOIUrl":"https://doi.org/10.1186/s10194-025-02032-0","url":null,"abstract":"","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":"26 1","pages":"94"},"PeriodicalIF":7.3,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12039078/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143975290","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":"Calcitonin gene-related peptide in newly diagnosed idiopathic intracranial hypertension: a prospective, cross-sectional, case-control study of cerebrospinal fluid and plasma.","authors":"Nadja Skadkær Hansen, Johanne Juhl Korsbaek, Lasse Kristoffer Bak, Niklas Rye Jørgensen, Dagmar Beier, Rigmor Højland Jensen","doi":"10.1186/s10194-025-02042-y","DOIUrl":"https://doi.org/10.1186/s10194-025-02042-y","url":null,"abstract":"<p><strong>Background: </strong>Calcitonin Gene-Related Peptide (CGRP) is involved in migraine pain signaling, and blockage hereof is effective in migraine treatment. Headache in idiopathic intracranial hypertension (IIH) is often migraine-like but the underlying mechanisms are not understood. We report levels of CGRP in plasma and cerebrospinal fluid (CSF) of patients with newly diagnosed IIH to elucidate CGRP involvement in the pathogenesis of headache in IIH.</p><p><strong>Method: </strong>We consecutively enrolled patients suspected of having IIH in a prospective cohort at two Danish tertiary headache centers. Patients are confirmed to have IIH or disproven of it (non-IIH). We included non-IIH with primary headache disorders as headache controls to IIH cases. We also recruited sex-, age- and BMI-matched healthy controls (HC). All participants had CSF and blood drawn and CGRP was analyzed using a validated radioimmunoassay. CSF plasma-ratios were calculated. Between-group levels were compared with ANOVA or Kruskal-Walli's test. In sub-analyses we restricted comparison of HC to non-IIH/IIH with chronic migraine; we also compared IIH with versus without headache. We correlated CGRP to lumbar opening pressure (OP), and BMI, and assessed the correlation between CGRP in plasma and CSF. Generalized or linear regression was applied to adjust for confounding by BMI, age, and active smoking.</p><p><strong>Results: </strong>Comparing 97 patients with IIH, 52 non-IIH, and 37 HC, we found no between-group differences in CGRP levels in plasma (p = 0.78), CSF (p = 0.79), or in CSF:plasma-ratio (p = 0.13). Adjusting for BMI, age, and smoking yielded similar results. CGRP levels were neither associated with having a migraine phenotype or chronic headache, nor with having any headache versus no headache in IIH. CGRP in plasma correlated with CGRP in CSF (p < 0.0001). CGRP did not correlate with OP or BMI.</p><p><strong>Conclusion: </strong>CGRP levels in plasma and CSF and their ratios were comparable in IIH, non-IIH patients with headache, and sex-, age-, and BMI-matched HC. CGRP in plasma correlated with CGRP in CSF. Due to methodology, we probably measured basal resting CGRP. The role of CGRP in IIH-headache needs further clarification. A headache preventive effect in IIH of anti-CGRP targeted therapy remains a relevant unexplored area.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":"26 1","pages":"95"},"PeriodicalIF":7.3,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12039064/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144039712","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":"Signaling pathways and molecular mechanisms involved in the onset and progression of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL); a focus on Notch3 signaling.","authors":"Parasta Heidari, Motahareh Taghizadeh, Omid Vakili","doi":"10.1186/s10194-025-02025-z","DOIUrl":"https://doi.org/10.1186/s10194-025-02025-z","url":null,"abstract":"<p><p>Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an autosomal-dominantly inherited cerebral small-vessel disease (SVD). CADASIL has diverse clinical features such as migraine with aura, dementia, and recurrent strokes, and is caused by a pathogenic mutation in the NOTCH3 gene which encodes a transmembrane receptor found in smooth muscle cells of small arteries and pericytes of brain capillaries. Pathogenic mutations alter the number of cysteine residues in the extracellular domain of NOTCH3, leading to the abnormal accumulation of granular osmiophilic material in the vessels of affected individuals. In addition, potential signaling pathways, such as transforming growth factor beta (TGF-β), may be involved in pathogenesis of the disease. This review aims to elucidate these mechanisms, particularly NOTCH3, in the context of CADASIL pathogenesis, providing insight into the role of NOTCH3 signaling and discussing the significance of these pathways for potential future therapeutic interventions in CADASIL patients.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":"26 1","pages":"96"},"PeriodicalIF":7.3,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12042419/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144014138","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":"Is there a role of calcitonin gene-related peptide in cortical spreading depression mechanisms?- argument con.","authors":"Agustin Melo-Carrillo","doi":"10.1186/s10194-025-02012-4","DOIUrl":"https://doi.org/10.1186/s10194-025-02012-4","url":null,"abstract":"<p><p>Cortical spreading depression (CSD) is a wave of neuronal and glial depolarization followed by suppressed neural activity, thought to underlie migraine aura. While Calcitonin Gene-Related Peptide (CGRP) is well established in migraine pathophysiology, its role in CSD remains uncertain. This comment evaluates evidence suggesting that CGRP is not directly involved in CSD initiation or propagation but may contribute to nociceptive activation associated with migraine. While some studies report CGRP-related effects on CSD susceptibility, methodological limitations raise concerns about their interpretation. Electrophysiological data indicate that CGRP does not influence the ionic mechanisms driving CSD. However, CGRP plays a key role in sensitizing nociceptive neurons, and CGRP-targeting drugs effectively modulate migraine pain without altering CSD dynamics. Clinical findings further suggest that peripheral CGRP inhibition reduces headache burden, potentially allowing the brain to recover from chronic pain states. In conclusion, while CGRP is integral to migraine pain modulation, its direct involvement in CSD appears minimal, highlighting distinct pathways for aura and headache pathophysiology.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":"26 1","pages":"91"},"PeriodicalIF":7.3,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12036166/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144029328","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}