Neuropeptides and the Nodes of Ranvier in Cranial Headaches

The trigeminovascular system (TGV) comprise of the trigeminal ganglion with neurons and satellite glial cells, with sensory unmyelinated C-fibers and myelinated Aδ-fibers picking up information from different parts of the head and sending signals to the brainstem and the central nervous system. In this review we discuss aspects of signaling at the distal parts of the sensory fibers, the extrasynaptic signaling between C-fibers and Aδ-fibers, and the contact between the trigeminal fibers at the nerve root entry zone where they transit into the CNS. We also address the possible role of the neuropeptides calcitonin gene-related peptide (CGRP), the neurokinin family and pituitary adenylyl cyclase-activating polypeptide 38 (PACAP-38), all found in the TGV system together with their respective receptors. Elucidation of the expression and localization of neuropeptides and their receptors in the TGV system may provide novel ways to understand their roles in migraine pathophysiology and suggest novel ways for treatment of migraine patients.

Neurogenic Inflammation: The Participant in Migraine and Recent Advancements in Translational Research

Migraine is a primary headache disorder characterized by a unilateral, throbbing, pulsing headache, which lasts for hours to days, and the pain can interfere with daily activities. It exhibits various symptoms, such as nausea, vomiting, sensitivity to light, sound, and odors, and physical activity consistently contributes to worsening pain. Despite the intensive research, little is still known about the pathomechanism of migraine. It is widely accepted that migraine involves activation and sensitization of the trigeminovascular system. It leads to the release of several pro-inflammatory neuropeptides and neurotransmitters and causes a cascade of inflammatory tissue responses, including vasodilation, plasma extravasation secondary to capillary leakage, edema, and mast cell degranulation. Convincing evidence obtained in rodent models suggests that neurogenic inflammation is assumed to contribute to the development of a migraine attack. Chemical stimulation of the dura mater triggers activation and sensitization of the trigeminal system and causes numerous molecular and behavioral changes; therefore, this is a relevant animal model of acute migraine. This narrative review discusses the emerging evidence supporting the involvement of neurogenic inflammation and neuropeptides in the pathophysiology of migraine, presenting the most recent advances in preclinical research and the novel therapeutic approaches to the disease.

Sleep disturbance management in patients with trigeminal autonomic cephalalgias

Trigeminal autonomic cephalalgias (TACs) are rare but are the most intense primary headaches that severely limit patients’ ability to work and be socially active. This article reviews the modern classification of TACs, based on the International Classification of Headache Disorders-3, and the key differences between TAC types, as well as the pathophysiological mechanisms – the role of the trigeminovascular system, autonomic nervous system, hypothalamus and vagus nerve – and their relation to circadian rhythms. The sleep disturbances that can occur in patients with TACs, exacerbating the course of the disease, and the role of melatonin, hypothalamus and suprachiasmatic nucleus in these conditions are also discussed. In addition, current therapies for cluster headache are described, which include acute therapy and prophylactic therapy, with recommendations regarding the timing of prophylactic therapy discontinuation. The review also includes the available data on melatonin as well as new therapies such as CGRP monoclonal antibodies and neuromodulation, which includes the two most promising techniques: non-invasive vagus nerve stimulation and sphenopalatine ganglion microstimulation. Furthermore, the authors present the clinical case of a patient with chronic cluster headache, which was significantly reduced in frequency and intensity when melatonin was added to the therapy.

TRPA1-Mediated Src Family Kinases Activity Facilitates Cortical Spreading Depression Susceptibility and Trigeminovascular System Sensitization

Transient receptor potential ankyrin 1 (TRPA1) plays a role in migraine and is proposed as a promising target for migraine therapy. However, TRPA1-induced signaling in migraine pathogenesis is poorly understood. In this study, we explored the hypothesis that Src family kinases (SFKs) transmit TRPA1 signaling in regulating cortical spreading depression (CSD), calcitonin gene-related peptide (CGRP) release and neuroinflammation. CSD was monitored in mouse brain slices via intrinsic optical imaging, and in rats using electrophysiology. CGRP level and IL-1β gene expression in mouse trigeminal ganglia (TG) was detected using Enzyme-linked Immunosorbent Assay and Quantitative Polymerase Chain Reaction respectively. The results showed a SFKs activator, pYEEI (EPQY(PO3H2)EEEIPIYL), reversed the reduced cortical susceptibility to CSD by an anti-TRPA1 antibody in mouse brain slices. Additionally, the increased cytosolic phosphorylated SFKs at Y416 induced by CSD in rat ipsilateral cerebral cortices was attenuated by pretreatment of the anti-TRPA1 antibody perfused into contralateral ventricles. In mouse TG, a SFKs inhibitor, saracatinib, restored the CGRP release and IL-1β mRNA level increased by a TRPA1 activator, umbellulone. Moreover, umbellulone promoted SFKs phosphorylation, which was reduced by a PKA inhibitor, PKI (14–22) Amide. These data reveal a novel mechanism of migraine pathogenesis by which TRPA1 transmits signaling to SFKs via PKA facilitating CSD susceptibility and trigeminovascular system sensitization.

Neurogenic Inflammation: One of the Participants of Migraine and the Contribution of Translational Research

Migraine is a primary headache disorder characterized by unilateral throbbing, pulsing headache, which lasts for hours to days, and the pain can interfere with daily activities. It exhibits various symptoms, such as nausea, vomiting, sensitivity to light, sound, and odors and physical activity consistently contributes to worsening pain. Despite the intensive research, little is still known about the pathomechanism of migraine. It is widely accepted that migraine involves activation and sensitization of the trigeminovascular system. It leads to the release of several pro-inflammatory neuropeptides and neurotransmitters and causes a cascade of inflammatory tissue responses including vasodilation, plasma extravasation secondary to capillary leakage, edema, and mast cell degranulation. Convincing evidence obtained in rodent models suggests that neurogenic inflammation is assumed to contribute to the development of a migraine attack. Chemical stimulation of the dura mater triggers activation and sensitization of the trigeminal system and causes numerous molecular and behavioral changes; therefore, this is a relevant animal model of acute migraine. This review article discusses the emerging evidence supporting the involvement of neurogenic inflammation and neuropeptides in the pathophysiology of migraine, presenting the most recent advances in preclinical research and the novel therapeutic approaches to the disease.

CGRP and CGRP-receptor as targets of migraine therapy: Brain Prize-2021

Background : Migraine is a highly prevalent primary headache with an unclear pathomechanism. During the last 40 years numerous hypotheses have arisen, among them the theory of the trigeminovascular system is the primary one. It serves as a skeleton in successful preclinical studies and in the development of effective therapeutic options for migraine headache. Objective : The Brain Prize (awarded annually by the Lundbeck Foundation) is the most prestigious tribute in neuroscience. The winners in 2021 were Lars Edvinsson, Peter Goadsby, Michael Moskowitz and Jes Olesen. They are the fathers of the migraine pathomechanism which led to revolutionary new treatments. This review summarizes their landmark findings. Methods : Data related to this topic were reviewed from PubMed records published between 1979 and May 2021. Searches were based on preclinical and clinical studies in the covered field. The findings were listed in chronological order. From a therapeutic perspective, only randomized controlled trials and meta-analysis were discussed. Results: The calcitonin gene-related peptide-related pathogenesis of migraine is based on the activation of the trigeminovascular system. The therapeutic triad for migraine is triptans, gepants and calcitonin gene-related peptide-targeted monoclonal antibodies. Conclusion: In the past 40 years, the systematic work of leading headache scientists has resulted in robust theoretical and therapeutic knowledge in the preclinical and clinical study of migraine.

Understanding the link between obesity and headache- with focus on migraine and idiopathic intracranial hypertension

Background Obesity confers adverse effects to every system in the body including the central nervous system. Obesity is associated with both migraine and idiopathic intracranial hypertension (IIH). The mechanisms underlying the association between obesity and these headache diseases remain unclear. Methods We conducted a narrative review of the evidence in both humans and rodents, for the putative mechanisms underlying the link between obesity, migraine and IIH. Results Truncal adiposity, a key feature of obesity, is associated with increased migraine morbidity and disability through increased headache severity, frequency and more severe cutaneous allodynia. Obesity may also increase intracranial pressure and could contribute to headache morbidity in migraine and be causative in IIH headache. Weight loss can improve both migraine and IIH headache. Preclinical research highlights that obesity increases the sensitivity of the trigeminovascular system to noxious stimuli including inflammatory stimuli, but the underlying molecular mechanisms remain unelucidated. Conclusions This review highlights that at the epidemiological and clinical level, obesity increases morbidity in migraine and IIH headache, where weight loss can improve headache morbidity. However, further research is required to understand the molecular underpinnings of obesity related headache in order to generate novel treatments.

Temporary resolution of hemicrania continua following ipsilateral ear piercing

BackgroundHemicrania continua is an uncommon subtype of trigeminal autonomic cephalgia that exhibits dramatic therapeutic response to indomethacin. Unfortunately, indomethacin is associated with a range of adverse effects, including neuropsychiatric complications, which limits its use in many patients. Although no other effective pharmacologic agents exist, there is emerging evidence for interventional treatments such as occipital nerve and vagus nerve stimulation, which may act by modulating neural activity within the trigeminovascular system.CaseWe present a 30-year-old woman with long-standing refractory hemicrania continua who suffered adverse effects to indomethacin. She experienced temporary, but near-complete, symptom resolution following piercing of the crus of the ear helix ipsilateral to her headache, whereas contralateral piercing produced no benefit.ConclusionsTo our knowledge, this case is the first to describe a therapeutic benefit following ear piercing in a patient with trigeminal autonomic cephalgia. We argue that symptom relief was obtained through a similar mechanism to occipital or vagus nerve stimulation.

NSAIDs medication for headache as the presenting symptom with migraine and COVID‐19

Headache is one of the most prevalent disorders of the nervous system. Headache is also the most common symptom of a variety of diseases, 4Department of XXX, Faculty of XXX, City, Country including migraine, COVID-19. International Classification of Headache Disorders (ICHD) lists over a thousand different types of headaches. Migraine is a widely known type of primary headache. Much research supports that the enhancement in migraine intensity related to chronic migraine such as neurogenic neuroinflammation, possibly leading to increased cytokine expression via activation of protein kinases in neurons and glial cells of the trigeminovascular system like some of the other headache diseases. No currently drug class available, either specific (triptans, ergots) or non-specific (opioids, paracetamol, NSAIDs), is effective in all types of headaches, in all patients and all attacks of the same patient. However, non-steroidal anti-inflammatory drugs (NSAIDs) minimize prostaglandin synthesis by blocking cyclooxygenase, which is included in the pathophysiology of migraine headaches. We searched the employed source was The Journal of Headache and Pain database by using NSAIDs with Headache, Migraine, and COVID-19 keywords. The search was performed from April 2021 and included 2017-2018-2019- 2020-2021 (last five years) the studies and reviews from the Journal of Headache and Face Pain Sites. Additionally, we noted the published or on-going studies, eight of these, about NSAIDs information contain searches that exist in the 12th European Headache Federation Congress (jointly with 32nd National Congress of the Italian Society) Study of Headaches’ book. Also, we included relationship migraine with COVID-19 studies to highlight the connection between the headache, which is one of the most common symptoms of both migraine and COVID-19, and the importance of managing migraine pain with NSAIDs during corona processing.

Migraine and neuroinflammation: the inflammasome perspective

Background Neuroinflammation has an important role in the pathophysiology of migraine, which is a complex neuro-glio-vascular disorder. The main aim of this review is to highlight findings of cortical spreading depolarization (CSD)-induced neuroinflammatory signaling in brain parenchyma from the inflammasome perspective. In addition, we discuss the limited data of the contribution of inflammasomes to other aspects of migraine pathophysiology, foremost the activation of the trigeminovascular system and thereby the generation of migraine pain. Main body Inflammasomes are signaling multiprotein complexes and key components of the innate immune system. Their activation causes the production of inflammatory cytokines that can stimulate trigeminal neurons and are thus relevant to the generation of migraine pain. The contribution of inflammasome activation to pain signaling has attracted considerable attention in recent years. Nucleotide-binding domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3) is the best characterized inflammasome and there is emerging evidence of its role in a variety of inflammatory pain conditions, including migraine. In this review, we discuss, from an inflammasome point of view, cortical spreading depolarization (CSD)-induced neuroinflammatory signaling in brain parenchyma, the connection with genetic factors that make the brain vulnerable to CSD, and the relation of the inflammasome with diseases that are co-morbid with migraine, including stroke, epilepsy, and the possible links with COVID-19 infection. Conclusion Neuroinflammatory pathways, specifically those involving inflammasome proteins, seem promising candidates as treatment targets, and perhaps even biomarkers, in migraine.