論文

Background: People with migraine may prefer over-the-counter (OTC) drugs because of multiple reasons, but their overuse can cause medication overuse headaches. This analysis of the ObserVational survey of the Epidemiology, tReatment, and Care Of MigrainE (OVERCOME [Japan]) 2nd study describes the real-world use of OTC headache drugs and the challenges that potentially prevent people with migraine from accessing appropriate medical management in Japan. Methods: This analysis of the cross-sectional, population-based, nationwide online survey included adults with migraine. Respondents reported their experiences with prescription and OTC drugs for migraine, migraine-specific drug awareness, and attitude towards migraine. Subgroup analyses were performed based on the number of monthly headache days (MHD) and the frequency of OTC drug use/month. Results: The 19,590 respondents with migraine (68.8% female; mean [SD] age 40.5 [13.1] years) had mean (SD) 3.5 (5.2) MHDs; 29.0% consulted doctors in the past year for migraine. OTC drug use in the past year was common (≥ 62.1%) regardless of doctor consultation or number of MHDs. Among respondents who answered that they would usually use prescribed drugs when they have a migraine attack, 35.2% reported that they would typically use OTC drugs too. The frequency of OTC drug use was the same or higher than that of prescribed drugs in 51.3% of the respondents who consulted doctors in the past year. Only 14.6% of respondents discussed OTC drugs with doctors during consultations in the past year. Migraine-specific drug access and awareness were limited even among frequent OTC drug users (≥ 10 days/month); 18.2% used triptans, but 65.5% never heard of it. Among 37.1% of respondents who had hesitated to visit a doctor, ‘I could handle it myself with OTC medicine’ was the most common reason for hesitation (34.9%). Conclusion: OTC drug use is common among people with migraine; however, it is not frequently discussed with doctors. Many respondents, even those with frequent OTC drug use, did not have access or awareness of migraine-specific drugs. To prevent medication overuse for migraine, the use of OTC drugs should also be discussed and managed.

片頭痛は，Quality of life（QOL）を著しく低下させ得る「脳の病気」であり，我が国では約1,000万人もの患者がいる．急性期治療薬としてはトリプタン製剤が従来使用されており，2022年からはラスミジタンも加わった．予防療法については，2021年に登場したカルシトニン遺伝子関連ペプチド（calcitonin gene-related peptide：CGRP）関連抗体薬が著効し「人生が変わる」ような症例も経験する．片頭痛は緊張型頭痛と誤診されているケースも多いが，片頭痛と適切に診断し，片頭痛に特化した治療を提供していくことが重要である．

早朝に頭痛が集中している片頭痛患者を臨床において経験することがある.慶應義塾大学病院神経内科頭痛外来を通院している片頭痛患者のうち,頭痛ダイアリーや問診上,早朝頭痛が目立った8例について,特徴および閉塞性睡眠時無呼吸症候群(OSAS)との関連を検討した.8例中7例においてOSAS(6例が軽症,1例が中等症)を認めた.Apnea hypopnea indexと頭痛が早朝に生じる割合には正の相関傾向を示していた.OSASは片頭痛増悪因子となっている可能性もあり,早朝頭痛を認める片頭痛患者でOSAS合併例に対しての治療は今後の研究課題である.(著者抄録)

We examined the ability of trigeminal nerve activation to induce cortical spreading depression in rats. Capsaicin was injected into the bilateral plantar or whisker pad for either 4 or 6 days in rats. The number and duration of cortical spreading depressions induced by potassium were significantly increased in animals injected with capsaicin in the bilateral whisker pad compared with animals injected in the bilateral plantar or in controls, while administration of a GABAA receptor agonist decreased these effects. Repetitive nociceptive stimulation of the trigeminal nerve lowers the threshold for the induction of cortical spreading depression by altering GABAergic neuronal activity.

Capsaicin is an agonist of transient receptor potential cation channel subfamily V member 1 (TRPV1). Strong TRPV1 stimulation with capsaicin causes mitochondrial damage in primary sensory neurons. However, the effect of repetitive and moderate exposure to capsaicin on the integrity of neuronal mitochondria remains largely unknown. Our electron microscopic analysis revealed that repetitive stimulation of the facial skin of mice with 10 mM capsaicin induced short-term damage to the mitochondria in small-sized trigeminal ganglion neurons. Further, capsaicin-treated mice exhibited decreased sensitivity to noxious heat stimulation, indicating TRPV1 dysfunction, in parallel with the mitochondrial damage in the trigeminal ganglion neurons. To analyze the capsaicin-induced mitochondrial damage and its relevant cellular events in detail, we performed cell-based assays using TRPV1-expressing PC12 cells. Dose-dependent capsaicin-mediated mitochondrial toxicity was observed. High doses of capsaicin caused rapid destruction of mitochondrial internal structure, while low doses induced mitochondrial swelling. Further, capsaicin induced a dose-dependent loss of mitochondria and autophagy-mediated degradation of mitochondria (mitophagy). Concomitantly, transcriptional upregulation of mitochondrial proteins, cytochrome c oxidase subunit IV, Mic60/Mitofilin, and voltage-dependent anion channel 1 was observed, which implied induction of mitochondrial biogenesis to compensate for the loss of mitochondria. Collectively, although trigeminal ganglion neurons transiently exhibit mitochondrial damage and TRPV1 dysfunction following moderate capsaicin exposure, they appear to be resilient to such a challenge. Our in vitro data show a dose-response relationship in capsaicin-mediated mitochondrial toxicity. We postulate that induction of mitophagy and mitochondrial biogenesis in response to capsaicin stimulation play important roles in repairing the damaged mitochondrial system.

BACKGROUND AND PURPOSE: Intracranial aneurysm formation and rupture risk are, in part, determined by genetic factors and sex. To examine their role, we compared 3 mouse strains commonly used in cerebrovascular studies in a model of intracranial aneurysm formation and rupture. METHODS: Intracranial aneurysms were induced in male CD1 (Crl:CD1[ICR]), male and female C57 (C57BL/6NCrl), and male 129Sv (129S2/SvPasCrl or 129S1/SvImJ) mice by stereotaxic injection of elastase at the skull base, combined with systemic deoxycorticosterone acetate-salt hypertension. Neurological deficits and mortality were recorded. Aneurysms and subarachnoid hemorrhage grades were quantified postmortem, either after spontaneous mortality or at 7 to 21 days if the animals survived. In separate cohorts, we examined proinflammatory mediators by quantitative reverse transcriptase-polymerase chain reaction, arterial blood pressure via the femoral artery, and the circle of Willis by intravascular latex casting. RESULTS: We found striking differences in aneurysm formation, rupture, and postrupture survival rates among the groups. 129Sv mice showed the highest rates of aneurysm rupture (80%), followed by C57 female (36%), C57 male (27%), and CD1 (21%). The risk of aneurysm rupture and the presence of unruptured aneurysms significantly differed among all 3 strains, as well as between male and female C57. The same hierarchy was observed upon Kaplan-Meier analysis of both overall survival and deficit-free survival. Subarachnoid hemorrhage grades were also more severe in 129Sv. CD1 mice showed the highest resistance to aneurysm rupture and the mildest outcomes. Higher mean blood pressures and the major phenotypic difference in the circle of Willis anatomy in 129Sv provided an explanation for the higher incidence of and more severe aneurysm ruptures. TNFα (tumor necrosis factor-alpha), IL-1β (interleukin-1-beta), and CCL2 (chemokine C-C motif ligand 2) expressions did not differ among the groups. CONCLUSIONS: The outcome of elastase-induced intracranial aneurysm formation and rupture in mice depends on genetic background and shows sexual dimorphism.

Transient receptor potential melastatin 8 (TRPM8) is a nonselective cation channel that primarily detects the innocuous cold. In pathological conditions, TRPM8 plays a role in the development of cold hyperalgesia/allodynia. Nerve growth factor (NGF) is an important mediator involved in various pain disorders. In the present study, the NGF-TrkA pathway increased TRPM8 expression by stabilizing TRPM8 mRNA through the actions of phosphatidylinositol 3-kinase and p38 MAP kinase. Moreover, c-Jun N-terminal kinase and Src tyrosine kinase were identified as a positive and negative regulator of TRPM8 expression, respectively, via post-transcriptional mechanisms independent of mRNA stabilization. PTEN activity was found to increase protein TRPM8 expression. Calcium imaging confirmed that NGF induced TRPM8 functional upregulation. Time-lapse fluorescence microscopic analysis and a cell fractionation assay revealed that NGF promoted the trafficking of TRPM8 to the plasma membrane. In the presence of NGF, lysosome-associated membrane protein-2 (LAMP-2) was localized to TRPM8-positive dot-like and linear structures, the latter of which were observed in the periphery of the cytoplasm. It was inferred that LAMP-2 was involved in the vesicular transport of TRPM8. Pharmacological blockade of the proteasome with MG132 led to a further increase in NGF-induced TRPM8 expression, indicating that the proteasome system played a pivotal role in the degradation of TRPM8. Our findings provide novel insight into the signaling pathways involved in NGF-mediated TRPM8 upregulation and its reversion to the normal state.

OBJECTIVE: Cortical spreading depolarizations (CSDs) are intense and ubiquitous depolarization waves relevant for the pathophysiology of migraine and brain injury. CSDs disrupt the blood-brain barrier (BBB), but the mechanisms are unknown. METHODS: A total of six CSDs were evoked over 1 hour by topical application of 300 mM of KCl or optogenetically with 470 nm (blue) LED over the right hemisphere in anesthetized mice (C57BL/6 J wild type, Thy1-ChR2-YFP line 18, and cav-1-/- ). BBB disruption was assessed by Evans blue (2% EB, 3 ml/kg, intra-arterial) or dextran (200 mg/kg, fluorescein, 70,000 MW, intra-arterial) extravasation in parietotemporal cortex at 3 to 24 hours after CSD. Endothelial cell ultrastructure was examined using transmission electron microscopy 0 to 24 hours after the same CSD protocol in order to assess vesicular trafficking, endothelial tight junctions, and pericyte integrity. Mice were treated with vehicle, isoform nonselective rho-associated kinase (ROCK) inhibitor fasudil (10 mg/kg, intraperitoneally 30 minutes before CSD), or ROCK-2 selective inhibitor KD025 (200 mg/kg, per oral twice-daily for 5 doses before CSD). RESULTS: We show that CSD-induced BBB opening to water and large molecules is mediated by increased endothelial transcytosis starting between 3 and 6 hours and lasting approximately 24 hours. Endothelial tight junctions, pericytes, and basement membrane remain preserved after CSDs. Moreover, we show that CSD-induced BBB disruption is exclusively caveolin-1-dependent and requires rho-kinase 2 activity. Importantly, hyperoxia failed to prevent CSD-induced BBB breakdown, suggesting that the latter is independent of tissue hypoxia. INTERPRETATION: Our data elucidate the mechanisms by which CSDs lead to transient BBB disruption, with diagnostic and therapeutic implications for migraine and brain injury.

Spreading depression (SD) is a slowly propagating wave of near-complete depolarization of neurons and glial cells across the cortex. SD is thought to contribute to the underlying pathophysiology of migraine aura, and possibly also an intrinsic brain activity causing migraine headache. Experimental models of SD have recapitulated multiple migraine-related phenomena and are considered highly translational. In this review, we summarize conventional and novel methods to trigger SD, with specific focus on optogenetic methods. We outline physiological triggers that might affect SD susceptibility, review a multitude of physiological, biochemical, and behavioral consequences of SD, and elaborate their relevance to migraine pathophysiology. The possibility of constructing a recurrent episodic or chronic migraine model using SD is also discussed.

INTRODUCTION: Cortical spreading depression (CSD) has recently been shown to induce the release of the nuclear protein termed high-mobility group box 1 from neurons, causing activation of the trigeminovascular system. Here, we explored the effects of single and multiple cortical spreading depression inductions on high-mobility group box 1 (HMGB1) transcriptional activity relative to high-mobility group box 1 protein expression levels and intracellular localization in cortical neurons and astrocytes. METHODS: Single or multiple cortical spreading depression inductions were achieved by KCl application to the mouse cerebral cortex. The animals were sacrificed at 30 minutes, 3 hours and 24 hours after cortical spreading depression induction. High-mobility group box 1 expression levels were explored with in situ hybridization, Western blotting and immunostaining. RESULTS: Cortical spreading depression up-regulated high-mobility group box 1 transcriptional activity in neurons at 3 hours in a manner that was dependent on the number of cortical spreading depression inductions. At 24 hours, the high-mobility group box 1 transcriptional activity had returned to basal levels. Cortical spreading depression induced a reduction in high-mobility group box 1 protein expression at 3 hours, which was also dependent on the number of cortical spreading depression inductions. Following cortical spreading depression, the release of high-mobility group box 1 from the nucleus was observed in a small proportion of neurons, but not in astrocytes. CONCLUSION: Cortical spreading depression induced translocation of high-mobility group box 1 from neuronal nuclei, driving transcriptional up-regulation of high-mobility group box 1 to maintain protein levels.

Migraine is among the most common and disabling neurological diseases in the world. Cortical spreading depression (CSD) is a wave of near-complete depolarization of neurons and glial cells that slowly propagates along the cortex creating the perception of aura. Evidence suggests that CSD can trigger migraine headache. Experimental models of CSD have been considered highly translational as they recapitulate migraine-related phenomena and have been validated for screening migraine therapeutics. Here we outline the essential components of validated experimental models of CSD and provide a comprehensive review of potential modulators and targets against CSD. We further focus on novel interventions that have been recently shown to suppress CSD susceptibility that may lead to therapeutic targets in migraine.

Background Recent genome-wide association studies have identified transient receptor potential M8 ( TRPM8) as a migraine susceptibility gene. TRPM8 is a nonselective cation channel that mediates cool perception. However, its precise role in migraine pathophysiology is elusive. Transient receptor potential V1 (TRPV1) is a nonselective cation channel activated by noxious heat. Both TRPM8 and TRPV1 are expressed in trigeminal ganglion (TG) neurons. Methods We investigated the functional roles of TRPM8 and TRPV1 in a meningeal inflammation-based migraine model by measuring the effects of facial TRPM8 activation on thermal allodynia and assessing receptor coexpression changes in TG neurons. We performed retrograde tracer labeling to identify TG neurons innervating the face and dura. Results We found that pharmacological TRPM8 activation reversed the meningeal inflammation-induced lowering of the facial heat pain threshold, an effect abolished by genetic ablation of TRPM8. No significant changes in the heat pain threshold were seen in sham-operated animals. Meningeal inflammation caused dynamic alterations in TRPM8/TRPV1 coexpression patterns in TG neurons, and colocalization was most pronounced when the ameliorating effect of TRPM8 activation on thermal allodynia was maximal. Our tracer assay disclosed the presence of dura-innervating TG neurons sending collaterals to the face. Approximately half of them were TRPV1-positive. We also demonstrated functional inhibition of TRPV1 by TRPM8 in a cell-based assay using c-Jun N-terminal kinase phosphorylation as a surrogate marker. Conclusions Our findings provide a plausible mechanism to explain how facial TRPM8 activation can relieve migraine by suppressing TRPV1 activity. Facial TRPM8 appears to be a promising therapeutic target for migraine.