Headache Phase Of Migraine Research Articles

Yoga for Migraine Prevention: An Ancient Practice with Evidence for Current Use.

The objective of this study is to review the recent literature on yoga for migraine prevention either as adjuvant or standalone therapy. Yoga is one of the most widely used complementary and integrative medicine (CIM) therapies; clinicians should be familiar with yoga practice so that they can best advise interested patients. It is also important to assess study design and types of yoga offered. Using PubMed and Litmaps, research published from 2018 to 2023 addressing yoga and migraine was assessed. Two systematic reviews and six studies have recently been published on yoga as adjunctive migraine preventive treatment. There is class III evidence and a grade B recommendation for yoga as an adjunct migraine preventive treatment. Yoga has been shown to reduce headache frequency, disability, and likely also pain intensity and self-efficacy. Two studies (one in children and one in adults) suggested that yoga as standalone migraine preventive treatment reduces pain intensity, disability, and perceived stress. More research is needed on the long-term efficacy (including change in monthly migraine days specifically in addition to headache frequency) and adherence to yoga practice for the prevention of migraine. In addition, to our knowledge, there is no study evaluating yoga practice in the prodromal or headache phase of migraine as acute treatment.

The Role of Glial Cells in Different Phases of Migraine: Lessons from Preclinical Studies.

Migraine is a complex and debilitating neurological disease that affects 15% of the population worldwide. It is defined by the presence of recurrent severe attacks of disabling headache accompanied by other debilitating neurological symptoms. Important advancements have linked the trigeminovascular system and the neuropeptide calcitonin gene-related peptide to migraine pathophysiology, but the mechanisms underlying its pathogenesis and chronification remain unknown. Glial cells are essential for the correct development and functioning of the nervous system and, due to its implication in neurological diseases, have been hypothesised to have a role in migraine. Here we provide a narrative review of the role of glia in different phases of migraine through the analysis of preclinical studies. Current evidence shows that astrocytes and microglia are involved in the initiation and propagation of cortical spreading depolarization, the neurophysiological correlate of migraine aura. Furthermore, satellite glial cells within the trigeminal ganglia are implicated in the initiation and maintenance of orofacial pain, suggesting a role in the headache phase of migraine. Moreover, microglia in the trigeminocervical complex are involved in central sensitization, suggesting a role in chronic migraine. Taken altogether, glial cells have emerged as key players in migraine pathogenesis and chronification and future therapeutic strategies could be focused on targeting them to reduce the burden of migraine.

Meningeal P2X7 Signaling Mediates Migraine-Related Intracranial Mechanical Hypersensitivity.

Cortical spreading depolarization (CSD) is a key pathophysiological event that underlies visual and sensory auras in migraine. CSD is also thought to drive the headache phase in migraine by promoting the activation and mechanical sensitization of trigeminal primary afferent nociceptive neurons that innervate the cranial meninges. The factors underlying meningeal nociception in the wake of CSD remain poorly understood but potentially involve the parenchymal release of algesic mediators and damage-associated molecular patterns, particularly ATP. Here, we explored the role of ATP-P2X purinergic receptor signaling in mediating CSD-evoked meningeal afferent activation and mechanical sensitization. Male rats were subjected to a single CSD episode. In vivo, extracellular single-unit recording was used to measure meningeal afferent ongoing activity changes. Quantitative mechanical stimuli using a servomotor force-controlled stimulator assessed changes in the afferent's mechanosensitivity. Manipulation of meningeal P2X receptors was achieved via local administration of pharmacological agents. Broad-spectrum P2X receptor inhibition, selective blockade of the P2X7 receptor, and its related Pannexin 1 channel suppressed CSD-evoked afferent mechanical sensitization but did not affect the accompanying afferent activation response. Surprisingly, inhibition of the pronociceptive P2X2/3 receptor did not affect the activation or sensitization of meningeal afferents post-CSD. P2X7 signaling underlying afferent mechanosensitization was localized to the meninges and did not affect CSD susceptibility. We propose that meningeal P2X7 and Pannexin 1 signaling, potentially in meningeal macrophages or neutrophils, mediates the mechanical sensitization of meningeal afferents, which contributes to migraine pain by exacerbating the headache during normally innocuous physical activities.SIGNIFICANCE STATEMENT Activation and sensitization of meningeal afferents play a key role in migraine headache, but the underlying mechanisms remain unclear. Here, using a rat model of migraine with aura involving cortical spreading depolarization (CSD), we demonstrate that meningeal purinergic P2X7 signaling and its related Pannexin 1 pore, but not nociceptive P2X2/3 receptors, mediate prolonged meningeal afferent sensitization. Additionally, we show that meningeal P2X signaling does not contribute to the increased afferent ongoing activity in the wake of CSD. Our finding points to meningeal P2X7 signaling as a critical mechanism underlying meningeal nociception in migraine, the presence of distinct mechanisms underlying the activation and sensitization of meningeal afferents in migraine, and highlight the need to target both processes for effective migraine therapy.

Exploring the Experience of Neck Pain in Individuals With Episodic Migraine (P3-12.004)

Exploring the Experience of Neck Pain in Individuals With Episodic Migraine (P3-12.004)

Astrocytes mediate migraine-related intracranial meningeal mechanical hypersensitivity.

The genesis of the headache phase in migraine with aura is thought to be mediated by cortical spreading depression (CSD) and the subsequent activation and sensitization of primary afferent neurons that innervate the intracranial meninges and their related large vessels. Yet, the exact mechanisms underlying this peripheral meningeal nociceptive response remain poorly understood. We investigated the relative contribution of cortical astrocytes to CSD-evoked meningeal nociception using extracellular single-unit recording of meningeal afferent activity and 2-photon imaging of cortical astrocyte calcium activity, in combination with 2 pharmacological approaches to inhibit astrocytic function. We found that fluoroacetate and l-α-aminoadipate, which inhibit astrocytes through distinct mechanisms, suppressed CSD-evoked afferent mechanical sensitization, but did not affect afferent activation. Pharmacological inhibition of astrocytic function, which ameliorated meningeal afferents' sensitization, reduced basal astrocyte calcium activity but had a minimal effect on the astrocytic calcium wave during CSD. We propose that calcium-independent signaling in cortical astrocytes plays an important role in driving the sensitization of meningeal afferents and the ensuing intracranial mechanical hypersensitivity in migraine with aura.

Dizziness and vertigo during the prodromal phase and headache phase of migraine: A systematic review and meta-analysis.

To assess the proportion of individuals who report dizziness and/or vertigo during the prodromal phase or headache phase of migraine. The databases of MEDLINE and EMBASE were searched for studies on dizziness and/or vertigo during the prodromal phase or headache phase of migraine. Pooled relative frequencies were estimated using a random-effects meta-analysis. We identified nine articles eligible for inclusion. Of these, one study reported results for the prodromal phase, seven studies for the headache phase and one study for both the prodromal and headache phase. In the prodromal phase, 9.0% of individuals with migraine reported dizziness, while 3.3% reported vertigo. During the headache phase, relative frequency of dizziness ranged from 6.7% to 59.6%, while vertigo ranged from 6.4% to 44.7%. The meta-analysis showed a relative frequency of 35.7% for dizziness (95% CI = 13.7-61.5%, I2 = 99%) and 33.9% for vertigo (95% CI = 26.7-41.5%, I2 = 87%). Study quality was rated 5/9 or below for seven studies and 6/9 or above for two studies. We found that there is a scarcity of literature on dizziness and vertigo as prodromal- and headache-associated symptoms in individuals with migraine. Methodological variations confound comparisons of epidemiological patterns, although it appears that dizziness and vertigo are more frequent during the headache phase of migraine, compared with the prodromal phase. Future studies should ensure use of standardized definitions and rigorous methodology to enable accurate measurements of dizziness and vertigo in migraine.

An unusual presentation of retinal migraine: a case report

Background: Retinal migraine is a type of migraine with aura. It is a rare entity which presents as monocular symptoms, such as scotomas or blindness followed by headache phase of migraine. There are wide varieties of causes for monocular vision loss ranging from benign causes to very serious causes of blindness. Case Presentation: This is a case of 26-year-old female who presented with recurrent attacks of unilateral vision loss but it was not followed by headache which is a rare entity. On investigations, her complete blood picture, liver function tests, renal function tests, erythrocyte sedimentation rate, C-reactive protein, electrocardiography, echocardiography, anti-neutrophil antibody, carotid Doppler, and magnetic resonance imaging of brain were all normal. Conclusion: The diagnosis of retinal migraine was established and the patient was reassured and counseled in detail with the advice of follow-up.

A Possible Role of Amyloidogenic Blood Clotting in the Evolving Haemodynamics of Female Migraine-With-Aura: Results From a Pilot Study.

Introduction: Migraine is a debilitating primary headache disorder with a poorly understood aetiology. An extensive body of literature supports the theory of migraine as a systemic vascular inflammatory disorder characterised by endothelial dysfunction. It is also well-known that chronic inflammation results in an excessive burden of oxidative stress and therefore cellular dysfunction. In this study the effects of excessive oxidative stress through the phases of female migraine-with-aura (FMA) were evaluated by examining the health of the systems of haemostasis.Methods: Blood was obtained from 11 FMA patients at baseline and during the headache phase of migraine, as well as from 8 healthy age-matched female controls. Samples were analysed using thromboelastography (TEG) to evaluate viscoelastic profiles, light microscopy for erythrocyte morphology, Scanning Electron Microscopy (SEM) for erythrocyte and fibrin clot structure, confocal microscopy for β-amyloid detection in fibrin clots.Results: Viscoelastic profiles from platelet poor plasma showed decreased clot reaction times in FMA at baseline (95% CI [5.56, 8.41]) vs. control (95% CI [7.22, 11.68]); as well as decreased time to maximum thrombus generation for the same comparison (95% CI [6.78, 10.20] vs. [8.90, 12.96]). Morphological analysis of erythrocytes indicated widespread macrocytosis, poikilocytosis and eryptosis in the migraineurs. Analysis of fibrin networks indicated that this hypercoagulability may be a result of aberrant fibrin polymerisation kinetics caused by the adoption of a β-amyloid conformation of fibrin(ogen).Conclusion: The results reaffirm the hypercoagulable state in migraine, and would suggest that this state is most likely a result of a systemic inflammatory state which induces oxidative damage to both erythrocytes and fibrin(ogen) in female episodic migraine-with-aura. Furthermore, if the amylodogenic changes to fibrin(ogen) were observed in a larger cohort, this would support theories of micro-embolisation in migraine-with-aura.

Living with Burden of Migraine: The Analysis of "My Migraine Voice" Survey Results in Turkey.

Migraine is a common, chronic neurologic disease which causes serious social and economical disability at both the individual and the community level. The aim of this study was to interpret the data for Turkey from "My Migraine Voice," an online survey of individuals suffering from frequent migraine attacks (≥4 days/month with migraine headaches) who had not benefited from existing prophylactic therapies, conducted in 31 countries to investigate the burden of migraine for the individual and the society. Based on a set of predetermined criteria (90% of the patients must have used prophylactic therapy, and 80% of them must have needed to change therapy), patients who had ≥ 4 days in a month with migraine headache in the past 3 months were asked to take an online survey of 88 questions. The study included questions aimed at determining the burden of disease during not only the headache phase, but also the prodrome and postdrome phases, as well as a questionnaire for determining the Reduction of Overall Activity and Productivity at Work ((WPAI: GH). A total of 237 patients from Turkey were included in the study. 62% of the patients stated that they were severely or very severely disabled in their daily activities during the headache phase of migraine, and 31% and 34% of the patients reported that they were disabled during the prodrome and postdrome phases, respectively. 28% of the patients stated they had been receiving prophylactic therapy for more than 2 years, and only 84% of these patients reported complete or partial satisfaction with their current therapies. This value was as low as ~70% in patients in whom 2 or more previous drug treatments or therapies had failed. Actively-working patients reported that they had lost 21% of their time at work due to migraine, and the overall loss of workforce was 67%. This study showed that migraine can cause disability in an individual's private and professional lives during every stage of migraine, including the prodrome and postdrome phases. This finding will be important for designing future treatments aimed at enhancing the quality of life and productivity of patients who cannot adequately benefit from existing therapies.

Dissociation between CSD-Evoked Metabolic Perturbations and Meningeal Afferent Activation and Sensitization: Implications for Mechanisms of Migraine Headache Onset.

The onset of the headache phase during attacks of migraine with aura, which occur in ∼30% of migraineurs, is believed to involve cortical spreading depression (CSD) and the ensuing activation and sensitization of primary afferent neurons that innervate the intracranial meninges, and their related large vessels. The mechanism by which CSD enhances the activity and mechanosensitivity of meningeal afferents remains poorly understood, but may involve cortical metabolic perturbations. We used extracellular single-unit recording of meningeal afferent activity and monitored changes in cortical blood flow and tissue partial pressure of oxygen (tpO2) in anesthetized male rats to test whether the prolonged cortical hypoperfusion and reduction in tissue oxygenation that occur in the wake of CSD contribute to meningeal nociception. Suppression of CSD-evoked cortical hypoperfusion with the cyclooxygenase inhibitor naproxen blocked the reduction in cortical tpO2, but had no effect on the activation of meningeal afferents. Naproxen, however, distinctly prevented CSD-induced afferent mechanical sensitization. Counteracting the CSD-evoked persistent hypoperfusion and reduced tpO2 by preemptively increasing cortical blood flow using the ATP-sensitive potassium [K(ATP)] channel opener levcromakalim did not inhibit the sensitization of meningeal afferents, but prevented their activation. Our data show that the cortical hypoperfusion and reduction in tpO2 that occur in the wake of CSD can be dissociated from the activation and mechanical sensitization of meningeal afferent responses, suggesting that the metabolic changes do not contribute directly to these neuronal nociceptive responses.SIGNIFICANCE STATEMENT Cortical spreading depression (CSD)-evoked activation and mechanical sensitization of meningeal afferents is thought to mediate the headache phase in migraine with aura. We report that blocking the CSD-evoked cortical hypoperfusion and reduced tissue partial pressure of oxygen by cyclooxygenase inhibition is associated with the inhibition of the afferent sensitization, but not their activation. Normalization of these CSD-evoked metabolic perturbations by activating K(ATP) channels is, however, associated with the inhibition of afferent activation but not sensitization. These results question the contribution of cortical metabolic perturbations to the triggering mechanism underlying meningeal nociception and the ensuing headache in migraine with aura, further point to distinct mechanisms underlying the activation and sensitization of meningeal afferents in migraine, and highlight the need to target both processes for an effective migraine therapy.

Aura and Other Neurologic Dysfunction in or with Migraine.

Migraine can present with a wide range of neurological symptoms. Based on currently available data, the symptoms of typical migraine aura are most likely related to cortical spreading depression (CSD), and evidence supports that CSD can lead to trigeminovascular activation resulting in the headache phase of migraine. An alternative diagnosis to migraine aura should be considered if migrainous headaches present with transient neurological symptoms that have features inconsistent with aura.

CGRP and migraine.

Migraine has been estimated to be the seventh highest cause of disability worldwide, and the third most common disease worldwide after dental caries and tension type headache. However, the use of currently available acute and prophylactic medications to control this condition, such as 5-HT1 agonists (triptans) and beta-blockers, is limited by side effects and efficacy so that alternative and more specific treatments are required. More recently, an improved understanding of the pathophysiology of disease has allowed investigation of new therapeutic targets. The 37 amino acid neuropeptide calcitonin gene-related peptide (CGRP) has been shown to play a crucial role in the trigeminocervical complex pathway for nociception in the head. Studies have demonstrated elevated levels in the external jugular vein during the headache phase of migraine, with reduction following headache resolution. Furthermore, CGRP infusion triggers migraine type headache and subsequent treatment with triptans results in normalization of CGRP levels. This neuropeptide is therefore thought to have a central role in pain modulation as it participates in the neurovascular pathway and contributes to the vasodilation and neurogenic inflammation, which leads to migrainous attacks. Targeting CGRP may provide the ideal therapeutic tool needed for control of this common and debilitating illness. The three studies chosen for this month’s journal club are a small sample of the large amount of research being performed on CGRP. The first investigates whether its measurement can be used to classify migraine. The second and third articles are phase II clinical trials which investigate the use of CGRP antagonists and a monoclonal antibody CGRP

The nitric oxide synthase inhibitor and serotonin-receptor agonist NXN-188 during the aura phase of migraine with aura: A randomized, double-blind, placebo-controlled cross-over study

Background and aimsNXN-188 is a combined neuronal nitric oxide synthase (nNOS) inhibitor and 5HT-1B/1D receptor agonist which has previously shown efficacy in the acute treatment of migraine. Nitric oxide (NO) is involved in the pathogenesis of migraine pain and is formed after cortical spreading depression. Therefore NXN-188 could perhaps prevent the development of the headache phase in migraine with aura if taken during the aura. The aims of the present study were to evaluate the efficacy and safety of 600mg NXN-188 in the acute treatment of migraine when dosed during the aura. MethodsA single-centre, randomized, double-blind, placebo-controlled, two-way crossover trial. The study medication was taken during the aura and the patients kept a study diary for 48h post-dose. ResultsOf 615 patients screened, 50 patients were included in the study and randomized. Only 18 patients completed both treatments in compliance with the study procedures. 22% of patients reported freedom of headache at 2h after intake of NXN-188 compared with only 11% of patients after placebo. ConclusionThe dual-action drug NXN-188 with 5HT-1B/1D agonism and nNOS inhibition, taken orally during the aura phase did not have a statistically substantial effect on migraine headache in this study. This study was limited by a high drop-out rate and small sample of included patients who were able to complete the cross-over protocol. Therefore, efficacy of the treatment cannot be refuted with certainty. ImplicationsThis study illustrates the difficulties of doing well controlled studies in migraine patients with aura. nNOS inhibition is expected to be effective mostly in the aura phase, i.e. the oral administration may have had too slow pharmacokinetics to have effect. Parenteral administration may overcome this obstacle. 5HT-1B/1D agonism is not effective when dosed during migraine aura. Repeated dosing of the NXN-188 during and immediately following the aura may have exploited more the dual-action. The high drop-out rate may be reduced in future studies by having the patients familiarize themselves with the study procedure by filling out the attack report form while treating one attack with their own medication before entering the trial. A parallel group comparison may be a more effective trial design for treatment during an aura.

Transient Localized Wave Patterns and Their Application to Migraine

Transient dynamics is pervasive in the human brain and poses challenging problems both in mathematical tractability and clinical observability. We investigate statistical properties of transient cortical wave patterns with characteristic forms (shape, size, duration) in a canonical reaction-diffusion model with mean field inhibition. The patterns are formed by ghost behavior near a saddle-node bifurcation in which a stable traveling wave (node) collides with its critical nucleation mass (saddle). Similar patterns have been observed with fMRI in migraine. Our results support the controversial idea that waves of cortical spreading depression (SD) have a causal relationship with the headache phase in migraine and, therefore, occur not only in migraine with aura (MA), but also in migraine without aura (MO), i.e., in the two major migraine subtypes. We suggest a congruence between the prevalence of MO and MA with the statistical properties of the traveling waves’ forms according to which two predictions follow: (i) the activation of nociceptive mechanisms relevant for headache is dependent upon a sufficiently large instantaneous affected cortical area; and (ii) the incidence of MA is reflected in the distance to the saddle-node bifurcation. We also observed that the maximal instantaneous affected cortical area is anticorrelated to both SD duration and total affected cortical area, which can explain why the headache is less severe in MA than in MO. Furthermore, the contested notion of MO attacks with silent aura is resolved. We briefly discuss model-based control and means by which neuromodulation techniques may affect pathways of pain formation.

Comments on the review article ‘Antidromic vasodilatation and the migraine mechanism’ by Geppetti et al. in the Journal of Headache and Pain 2012; 13:103–111

The authors reviewed the role of antidromic vasodilatation in migraine, and concluded that the weight of evidence shows that the concept of antidromic vasodilatation in migraine cannot be discarded [1]. Unfortunately they included references that they wrongly claimed mitigate against the concept, weakening their position unnecessarily. In the section entitled ‘Neurogenic vasodilatation in migraine’, they state that Graham and Wolff’s proposal that the headache phase of migraine is associated with dilatation of the superficial temporal artery, was subsequently challenged by failure to measure significant vasodilatation during migraine (a) using Doppler flowmetry [2], and (b) using magnetic resonance angiography [3]. In fact in neither of these studies were the terminal branches of the external carotid artery studied. Zwetsloot studied the only middle cerebral artery and not the extracranial vessels, and Schoonman studied the intracranial vessels, and the last 10 mm of the external carotid before it divides into its terminal branches. This section of the external carotid artery has never been implicated in migraine, and is therefore irrelevant in any discussion of Graham and Woolf’s proven theory. The authors also cite the ‘lack of correlation between the degree of vasodilatation and the severity of headache’ as possibly challenging Woolf’s theory. Both studies that they cite, however, were on headache induced in healthy volunteers [4, 5], and not in migraineurs. Graham and Woolf’s findings relate to the temporal arteries in migraineurs, and should not be compared to the findings in non-migraineurs. The conclusion of Geppetti et al. that the concept of antidromic vasodilatation is valid is strengthened when the incorrect references are removed from the equation.

CGRP Receptor Antagonists: Toward a Novel Migraine Therapy

Migraine remains one of the most prevalent and disabling neurological disorders that often affects a person during their most productive years. Migraine afflicts approximately 11% of the adult population globally, causes substantial disability, which translates into lost productivity both at home and at work. Clearly there remains a need for new approaches to treat migraine and calcitonin gene-related peptide (CGRP) receptor antagonists have the potential to be a major advance in antimigraine therapy. CGRP was first proposed to play a role in migraine pathophysiology a little over 20 years ago and today there is considerable evidence that CGRP plays a key role in the pathogenesis of migraine. CGRP is a 37 amino acid vasoactive neuropeptide largely expressed in sensory neurons. It was observed that plasma levels of CGRP were elevated during the headache phase of migraine and the levels were normalized concomitantly with pain relief. This observation, along with other evidence, suggested that CGRP receptor antagonists might represent a novel approach to migraine treatment. The advent of small molecule CGRP receptor antagonists has clearly demonstrated a clinical link between blocking the CGRP receptor and effectiveness in treating migraine. This review will highlight the biology of CGRP as it pertains to migraine; discuss the CGRP receptor; spotlight the development of CGRP receptor antagonists; and examine site of action.

Neuropeptides and Other Chemical Mediators, and the Role of Anti-inflammatory Drugs in Primary Headaches

Primary headaches including the migraine, cluster, and tension headaches are common neurological disorders which cause pain and disability to the patients. The pathomechanism of migraine is not very well understood however, current clinical findings indicate a possible primary brain disorder due to activation of the brain and brainstem as triggers for migraine. The headache phase of migraine may be due to activation of the peripheral nerves including the trigeminal nerve and others innervating the cranial blood vessels and release of vasoactive substances including the calcitonin generelated peptides (CGRP), possibly leading to vasodilation and brainstem activation. Several of our studies in an experimental model of pain using electrical stimulation of the trigeminal ganglion in rats focused on various neuropeptides release from the peripheral and central trigeminal nerve terminals, however, clinically only the CGRP in migraine and CGRP and vasoactive intestinal peptide (VIP) in cluster headache were found in patient’s blood. Although several drugs are used in the treatment of migraine, the non-steroid anti-inflammatory drugs (NSAIDs) and the triptan family of drugs are the first choice drugs recommended for the treatment of acute migraine headache. Although clinically very few studies detected other vasoactive/inflammatory molecules in the blood of migraine patients, sensitization of peripheral axons can involve many inflammatory mediators affecting the peripheral tissue substrates of pain. Moreover, central sensitization in the trigeminal nucleus can also contribute to additional pain responses. This article reviews neuropeptides and other molecules involved in primary headaches and major drugs proposed for their treatment in recent years. Keywords: Neuropeptide, Headache, Anti-inflammatory drugs.

Clinical characteristics of migraine concordant monozygotic twin pairs.

The aim of the study was to search for clinical differences between migraine with and without aura. From a population-based Finnish Twin Cohort we studied 51 migraine concordant monozygotic twin pairs. There were 20 pairs concordant for migraine with aura, 6 pairs concordant for migraine without aura and 12 "mixed" pairs. In the remaining 13 pairs the aura of at least 1 twin could not be classified. All 20 migraine with aura pairs were concordant for visual aura and 19 for moderate or severe headache while all 6 pairs with migraine without aura were concordant for headache duration of 4 to 24 h, moderate or severe headache and nausea. The 12 "mixed" pairs had more often unilateral and pulsating headache compared to both the migraine with or without aura pairs. Overall individual migraine with aura twins had more photophobia (P = 0.032) and the migraine without aura twins more nausea (P = 0.025). The difference between migraine with and without aura is not explained entirely by genetical factors: 12 genetically identical twin pairs were discordant for the aura. The headache phase in migraine with and without aura is very similar, but not identical. Probably there are several and different liability loci for the migraine aura and the migraine headache. The distribution of these several loci along with acquired factors will decide whether the phenotype is migraine with or without aura.

Role of neuropeptides in migraine: where do they stand in the latest expert recommendations in migraine treatment?

AbstractMany factors have been implicated in the pathogenesis of migraine headache, including activation of the trigeminovascular system, dysfunction of: cerebral blood vessels, circulating vasoactive substances, mitochondrial energy metabolism, brain oxygenation and metabolism, platelet disorder, alterations in serotonin levels, low levels of brain tissue magnesium, altered transport of ions across the cell membrane, and inheritance and dysfunction of the brainstem periaqueductal gray matter. The headache phase of migraine is associated with cerebral vasodilation and inflammation, presumably mediated by the release of vasoactive substances and neuropeptides including CGRP (calcitonin gene‐related peptide). Increased serum CGRP levels have been detected during migraine and cluster headache. One strategy to treat migraine is to inhibit the release of neuropeptides or to block their receptors. This article briefly reviews some experimental and clinical investigations focused on neuropeptide involvement in migraine. Drug Dev Res 68:294–314, 2007. © 2007 Wiley‐Liss, Inc.

Characterisation of CGRP receptors in the human isolated middle meningeal artery

Although the understanding of migraine pathophysiology is still incomplete, there seems to be little doubt that dilatation of cranial blood vessels, including meningeal arteries, is involved in the headache phase of migraine. Since calcitonin gene-related peptide (CGRP) has been implicated in this vasodilatation, the present study set out to compare the relaxant effects of the endogenous ligand h-αCGRP, and [ethylamide-Cys 2,7]h-αCGRP ([Cys(Et) 2,7]h-αCGRP), a CGRP 2 receptor agonist, on human isolated middle meningeal artery segments, precontracted with KCl. Classical Schild plot analysis was used to characterise the receptor population in this artery using BIBN4096BS and h-αCGRP 8–37 as antagonists. h-αCGRP relaxed arterial segments more potently than [Cys(Et) 2,7]h-αCGRP (pEC 50: 8.51 ± 0.16 and 7.48 ± 0.24, respectively), while the maximal responses to these agonists were not significantly different. BIBN4096BS equipotently blocked the relaxations induced by both agonists with a p A 2 of ∼ 10 and with a Schild plot slope not significantly different from unity. h-αCGRP 8–37 also antagonised the response to h-αCGRP with a p A 2 of 6.46 ± 0.16 and a Schild plot slope not different from unity. Furthermore, the results obtained from RT-PCR studies confirmed the presence of all the essential components required for a functional CGRP 1 receptor in these arteries. Considering the high antagonist potency of BIBN4096BS, coupled to the lower agonist potency of [Cys (Et) 2,7]h-αCGRP, it is reasonable to suggest a predominant role of CGRP 1 receptors in the human middle meningeal artery. This view is reinforced by Schild plot analysis, which revealed a slope of unity in all experiments, giving further evidence for a homogeneous CGRP receptor population in this vascular preparation.