Journal of Headache and Pain最新文献

Background: Vestibular migraine (VM) is a disorder characterized by recurrent episodes of dizziness or vertigo and is often accompanied by headache. The mechanisms underlying vestibular dysfunction and pain in VM remain unclear.

Methods: Chronic migraine (CM) and VM models were induced by NTG and kainic acid, respectively. Behavioral assessments were conducted to evaluate vestibular dysfunction and pain in the VM and CM models. Transmission electron microscopy (TEM) was used to examine peripheral receptor impairment. Immunofluorescence, including staining for Cellular Proto-oncogene (c-Fos), Neuronal Nuclei (NeuN), and calcitonin gene-related peptide (CGRP), identified activated brain regions such as the cortex, midbrain, and cerebellum. Multiplex immunohistochemistry and cholera toxin subunit B (CTB) tracing were performed to analyze nuclear heterogeneity and neural communication. Additionally, RNA sequencing (RNA-Seq) and Ionized calcium-binding adapter molecule 1 (IBA1) immunostaining were used to investigate ion channel expression in the spinal trigeminal nucleus caudalis (Sp5c).

Results: CM and VM-related behaviors, such as allodynia and balance disturbance, were successfully reproduced in mouse model. TEM revealed significant damage to peripheral sensory receptors, particularly in the trigeminal ganglion and cochlear cells. Distinct activation patterns of c-Fos and CGRP were observed in VMs and CMs. CTB tracing confirmed that signals are transmitted from the vestibulocerebellum (VbC) to the Sp5c via the vestibular nuclei (VN). Furthermore, RNA-Seq combined with coimmunostaining revealed an increased expression of transient receptor potential vanilloid 2 (TRPV2) ion channels in microglia within Sp5c, indicating their potential role in VM pathology.

Conclusions: This study preliminarily explored VbC-VN-Sp5c communication and identified TRPV2 ion channels in microglia as key players in neuron-glia crosstalk in VM. These findings provide new insights into the mechanisms underlying vestibular migraine and suggest potential therapeutic targets.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) show substantial efficacy in regulating blood glucose levels and lipid metabolism, initially as an effective treatment for diabetes mellitus. In recent years, GLP-1RAs have become a focal point in the medical community due to their innovative treatment mechanisms, robust therapeutic efficacy, and expansive development prospects. Notably, GLP-1RAs benefit pain management through their neuroprotective and metabolic regulatory properties, such as inhibiting inflammation responses and oxidative stress, promoting β-endorphin release and modulating several other crucial biological pathways. Hence GLP-1RAs hold promise for repurposing as treatments for pain disorders. In this narrative review, we thoroughly trace the current preclinical and clinical evidence of seven pain modalities, including inflammatory pain, osteoarthritis, visceral pain, neuropathic pain, diabetic neuropathy, cancer pain and headache, to support the efficacy and underlying biological mechanisms of GLP-1RAs as therapeutic agents for pain suffering. Despite these promising findings, further research is necessary to establish their long-term efficacy, optimal dosing strategies, and potential synergistic interactions of GLP-1RAs with existing pain management therapies. Future clinical trials should aim to distinguish the direct analgesic effects of GLP-1RAs from their metabolic benefits and explore their broader applications in pain conditions. The ongoing exploration of new indications for GLP-1RAs further highlights their transformative potential in advancing medical treatments across diverse clinical fields.

Background: Migraine is a common type of primary headache which is responsible for one-third of the headache cases. It's also considered the third highest neurological disease with disability in 2021, however, underdiagnosis of migraine remains a significant health problem. This study aims to assess the prevalence of hidden migraine identified by screening among the Arab general population, describe the characteristics of headache attacks, and assess disability and distress associated with migraine.

Methods: This cross-sectional study was conducted between April and June 2024 among the general population of eight Arab countries using a self-administered online questionnaire to collect sociodemographic data and medical history. The questionnaire also included the ten-item Kessler Psychological Distress Scale (K10), Migraine Screen Questionnaire (MS-Q), and Migraine Disability Assessment Questionnaire (MIDAS).

Results: A total of 2152 individuals completed the questionnaire with a median age of 24 (21-29). Among them 683 (31.7%) individuals were screened positive by MS-Q. Using regression analysis, the independent predictors for positive screening were being Saudi Arabian, having one or more diseases, and having severe psychological distress with adjusted odds ratios of 0.622, 0.282, and 1.329 respectively. Among positive cases, 667 (97.7%) reported having headaches in the past 3 months. Phonophobia (50.97%) and photophobia (49.33%) were the most common associated symptoms. Sleep disturbance (66.72%) and noise (63.87%) were the most common triggering factors while sleep (71.81%) and self-medication (68.52%) were the most common relieving factors. Only 25.34% reported having aura with the last attack. According to MIDAS scores, 459 (67.2%) positive cases had moderate or severe disabilities. Regression analysis identified being a housewife and having one or more diseases as the independent predictors of having moderate or severe disabilities with adjusted odds ratios of 0.228 and 0.523 respectively.

Conclusion: Migraine is still underdiagnosed in Arab countries which causes significant disability among positive cases. Raising awareness about the importance of early migraine diagnosis is crucial for encouraging the general population to seek medical advice once they have symptoms.

Background: Medication-overuse headache (MOH) is the most common secondary headache disorder, resulting from or leading to the frequent use of acute headache medications. Despite the availability of various treatment strategies, the optimal approach remains uncertain.

Objective: This network meta-analysis (NMA) aimed to evaluate the comparative efficacy of different strategies for managing MOH, focusing on reducing monthly headache days.

Methods: We systematically reviewed randomized controlled trials (RCTs) comparing withdrawal strategies, including bridging therapies, the use of concurrent migraine prevention drugs, and additional education, in adult patients diagnosed with MOH. The primary outcome was the reduction in monthly headache days. Eligible studies were analyzed using a random-effects NMA model, integrating both direct and indirect evidence. Treatments were ranked using p-scores, and risk of bias was assessed using the Cochrane risk of bias tool 2.0.

Results: Sixteen RCTs involving 3,000 participants were included. Compared to control, combination therapies, such as abrupt withdrawal with oral prevention and greater occipital nerve block and restriction of overused acute medication with oral prevention and Calcitonin gene-related peptide (CGRP) therapies, demonstrated the greatest efficacy, with reductions in monthly headache days of -10.6 (95% CI: [-15.03; -6.16]) and -8.47 (95% CI: [-12.78; -4.15]), respectively. Headache prevention strategies, including oral prevention (P), anti-calcitonin gene-related peptide (receptor) (CGRP(R)) therapies (A), and botulinum toxin (B) showed significant in reduction of monthly headache days, but no single initial prevention strategy demonstrates superior efficacy over the others. In contrast, abrupt withdrawal alone (W) showed no significant efficacy, with a mean difference of -2.77 (95% CI: [-5.74; 0.20]).

Conclusion: Combination therapies, including anti-CGRP(R) therapies and nerve blocks, appear to be the most effective strategies for MOH management, highlighting their potential as initial treatment options. While headache prevention strategies demonstrated similar efficacy, abrupt withdrawal alone was insufficient. The observed reduction in headache frequency after treatment suggests that strategies with greater efficacy may help lower the likelihood of MOH relapse.

Trial registration: PROSPERO, CRD 42024620487.

Background: Migraine is the second disabling neurological disorder with a high prevalence. Aura occurs in one-third of migraineurs and visual aura accounts for over 90%. Cortical spreading depression (CSD) underlies aura and might trigger migraine headaches. Compared with CSD induction by invasive electrical, chemical, or mechanical stimulation, optogenetics avoids direct influences on meninges in the stimulation process. However, previous optogenetic CSD models mainly use Thy1-ChR2-YFP or CaMKIIα-cre transgenic mice. They are limited when the pathogenesis study requires transgenic mice to express other specific promotor, such as the dopamine or serotonin transporter promotor. In addition, reported behavioral paradigms were based on CSD induction under anesthesia. This study aimed to establish an optogenetic CSD-induced migraine model originating in the primary visual cortex (VISp) in C57BL/6 J mice and presented the behavioral paradigm when CSD induction was under awake condition.

Methods: We performed viral transduction for the expression of light-sensitive channelrhodopsin-2 in pyramidal neurons of VISp in C57BL/6 J mice. Regional cerebral blood flow (rCBF) was measured by laser speckle flowmetry to confirm CSD induction. The von Frey, light-dark box, elevated plus maze, and open field test were conducted to verify migraine-related behaviors in freely moving mice.

Results: An optogenetic stimulus induced typical spreading triphasic rCBF change with a reduction of over 20%, confirming CSD induction. A single unilateral CSD in freely moving C57BL/6 J mice triggered bilateral periorbital and hind-paw allodynia lasting for 4-24 h. Notably, the ipsilateral periorbital mechanical threshold was significantly lower than the contralateral at 1 h. It also generated photophobia and anxiety behaviors persisting for 24-48 h. Furthermore, cutaneous allodynia and anxiety behaviors were alleviated by sumatriptan.

Conclusions: This study proposes an optogenetic CSD-induced migraine model originating from VISp in awake and freely moving C57BL/6 J mice and presents the behavioral paradigm in detail. The CSD model in wild-type mice is promising to be wildly used to study the pathogenesis of MwA.

Background: Trigeminal neuropathic pain (TNP) is a chronic condition characterized by heightened nociceptive responses and neuroinflammatory changes. While astrocytes are recognized as critical players in pain modulation, their specific role in influencing descending trigeminal pain pathways via ventrolateral orbitofrontal cortex (vlOFC) activity modulation remains underexplored. Therefore, we investigated the impact of optogenetic modulation of astrocytes in the vlOFC on pain hypersensitivity in a rat model of chronic constriction injury of the infraorbital nerve (CCI-ION).

Method: Adult female Sprague Dawley rats underwent ION constriction to mimic TNP symptoms, with naive and sham animals serving as controls. AAV8-GFAP-hChR2-mCherry, AAV8-GFAP-eNpHR3.0-mCherry, or AAV8-GFAP-mCherry were delivered to the vlOFC for in vivo optogenetic manipulation. Pain behaviors were assessed using acetone, von Frey, and elevated plus maze tests, while electrophysiological recordings from the ventrolateral periaqueductal gray (vlPAG) and ventral posteromedial (VPM) thalamus were obtained.

Results: Orofacial hyperalgesia, reduced vlPAG activity, and thalamic hyperexcitability were associated with vlOFC astrocytic hyperactivity in the TNP animals. In contrast, optogenetic inhibition of vlOFC astrocytes restored vlOFC glutamatergic signaling, increased vlPAG glutamatergic neuronal activity, and reduced hyperactivity in the VPM thalamus. Behavioral assessments also revealed alleviation of hyperalgesia, allodynia, and anxiety-like behaviors during the stimulation-ON phase, alongside reduced neuroinflammatory markers, including P2 × 3 and Iba-1. However, astrocytic excitation and null virus controls did not alter TNP responses, underscoring the specificity of astrocytic inhibition.

Conclusion: These findings suggest that the astrocytic subpopulation in the vlOFC and its robust influence on vlPAG glutamatergic neurons play a crucial role in restoring descending pain processing pathways, potentially contributing to the development of novel therapeutic approaches for TNP management.

Background: Although peripheral administration of pregnenolone sulfate (PS) has been reported to produce pronociceptive effects, the mechanisms by which PS modulates the excitability of nociceptive neurons are poorly understood. Here, we report on the excitatory role of PS in peripheral nociceptive neurons, focusing on its effects on tetrodotoxin-resistant (TTX-R) Na⁺ channels.

Methods: TTX-R Na⁺ current (I_Na) mediated by Na_V1.8 was recorded from acutely isolated small-sized dural afferent neurons of rats, identified with the retrograde fluorescent dye DiI, using a whole-cell patch-clamp technique.

Results: Transcripts for enzymes and transporters involved in PS biosynthesis were detected in the ophthalmic branch of the trigeminal ganglia. In voltage-clamp mode, PS preferentially potentiated the TTX-R persistent I_Na, a small non-inactivating current during sustained depolarization. PS shifted the voltage-inactivation relationship toward a depolarizing range. PS also delayed the onset of inactivation and accelerated the recovery from inactivation of TTX-R Na⁺ channels. Additionally, PS decreased the extent of use-dependent inhibition of TTX-R Na⁺ channels. In current-clamp mode, PS hyperpolarized dural afferent neurons by increasing the leak K⁺ conductance. Nevertheless, PS decreased the rheobase current-the minimum current required to generate action potentials-and increased the number of action potentials elicited by depolarizing current stimuli.

Conclusion: We have shown that the excitatory neurosteroid PS preferentially potentiates TTX-R persistent I_Na and reduces the inactivation of TTX-R Na⁺ channels, resulting in increased excitability of dural afferent neurons. The potential role of endogenous PS in migraine pathology warrants further investigation.

Transient Receptor Potential Melastatin 3 (TRPM3) channels are Ca²⁺ permeable ion channels that act as polymodal sensors of mechanical, thermal, and various chemical stimuli. TRPM3 channels are highly expressed in the trigeminovascular system, including trigeminal neurons and the vasculature. Their presence in dural afferents suggests that they are potential triggers of migraine pain, which is originating from the meningeal area. This area is densely innervated by autonomous and trigeminal nerves that contain the major migraine mediator calcitonin gene-related peptide (CGRP) in peptidergic nerve fibers. Co-expression of TRPM3 channels and CGRP receptors in meningeal nerves suggests a potential interplay between both signalling systems. Compared to other members of the TRP family, TRPM3 channels have a high sensitivity to sex hormones and to the endogenous neurosteroid pregnenolone sulfate (PregS). The predominantly female sex hormones estrogen and progesterone, of which the levels drop during menses, act as natural inhibitors of TRPM3 channels, while PregS is a known endogenous agonist of these channels. A decrease in sex hormone levels has also been suggested as trigger for attacks of menstrually-related migraine. Notably, there is a remarkable sex difference in TRPM3-mediated effects in trigeminal nociceptive signalling and the vasculature. In line with this, the relaxation of human isolated meningeal arteries induced by the activation of TRPM3 channels is greater in females. Additionally, the sex-dependent vasodilatory responses to CGRP in meningeal arteries seem to be influenced by age-related hormonal changes, which could contribute to sex differences in migraine pathology. Consistent with these observations, activation of TRPM3 channels triggers nociceptive sensory firing much more prominently in female than male mouse meninges, suggesting that pain processing in female patients with migraine may differ. Overall, the combined TRPM3-related neuronal and vascular mechanisms could provide a possible explanation for the higher prevalence and even the more severe quality of migraine attacks in females. This narrative review summarizes recent data on the sex-dependent roles of TRPM3 channels in migraine pathophysiology, the potential interplay between TRPM3 and CGRP signalling, and highlights the prospects for translational therapies targeting TRPM3 channels, which may be of particular relevance for women with migraine.

Background: Migraine is a chronic neurological condition that has a well-documented, yet not fully understood connection to stroke, particularly in patients who experience migraine with aura (MA). Although migraine can rarely be directly related to stroke, in the form of migrainous infarction, it serves as an independent risk factor, particularly when combined with other factors such as smoking or hypertension. This study will thoroughly review and summarize the existing literature regarding the relationship between migraine and stroke.

Main text: Several key processes are common to both stroke and migraine. These include cortical spreading depression, particularly in MA, endothelial dysfunction, which activates local inflammatory responses, and vasculopathy, which often appears as white matter hyperintensities on neuroimaging. Furthermore, microRNAs also play a significant role in the pathogenesis of both migraine and stroke by targeting genes such as CALCA, which regulates calcitonin gene-related peptide, a factor involved in the pathophysiology of both conditions. There are also several genetic links between migraine and stroke, including both monogenic diseases and common risk loci. Moreover, various conditions are linked to both migraine and stroke, including patent foramen ovale (PFO), atrial fibrillation, carotid artery dissection, platelet dysfunction, dyslipidemia, obesity, hyperhomocysteinemia, and elevated estrogen levels, such as in combined hormonal contraceptives. Notably, PFO is often found in patients who have experienced a cryptogenic stroke, as well as in those with MA. While microemboli associated with PFO may provoke ischemic events and migraine attacks, the effectiveness of PFO closure in alleviating migraine symptoms has produced varying results. Migraine is linked to worse outcomes after ischemic stroke, including larger stroke volumes and poorer functional outcomes, while the connection between migraines and hemorrhagic stroke is less understood. Furthermore, migraine may serve as a stroke mimic (condition presenting with symptoms similar to ischemic stroke) or a stroke chameleon (unrecognized stroke misdiagnosed as migraine), leading to significant diagnostic and treatment errors.

Conclusions: The interplay between migraine and stroke is complex, involving shared pathophysiology and overlapping risk factors. While migraine can serve as both a cause and a risk factor for stroke, the precise mechanisms remain unclear, warranting further research to clarify their connection and enhance clinical management.