Novelty in Inflammation and Immunomodulation in Migraine

2019 ◽  
Vol 25 (27) ◽  
pp. 2919-2936 ◽  
Author(s):  
Cinzia Cavestro ◽  
Marcella Ferrero ◽  
Silvia Mandrino ◽  
Marco Di Tavi ◽  
Eugenia Rota
Keyword(s):  
Inflammatory Pain ◽  
Botulinum Toxin Type A ◽  
Botulinum Toxin Type ◽  
Trigeminovascular System ◽  
Calcitonin Gene ◽  
Pituitary Adenylate Cyclase ◽  
Pain Pathway ◽  
And Function ◽  
New Hypothesis ◽  
Immunomodulating Drugs

Background.: Migraine is a diffuse and disabling disease. Its pathophysiology is complex and involves both central and peripheral dysfunctions. Objective.: This review will discuss the pathogenesis of migraine from the origin of the neuro-inflammatory theory, to the modern pathophysiological model and the latest therapies. Methods.: PUBMED and EMBASE (up to May 2019) were searched for: migraine, inflammation, immunomodulation. An additional search was carried out from the bibliography of previous review articles. Results.: Migraine was thought to be mainly a vascular disorder, according to the so-called “vascular theory”. Based on animal models, a new hypothesis called “the neuro-inflammatory” was conceived at the end of the 20th century. The growing knowledge about the trigeminovascular system and its role in the inflammatory-pain pathway, allowed to identify other specific neurotransmitters, such as the Calcitonin Gene-Related Peptide and Pituitary Adenylate Cyclase-Activating Peptide. Evidence was provided that the inflammatory-pain system could become sensitised and, due to this sensitisation, the pain could also perpetuate, even in the absence of any triggers of the migraine attack. At last, brain immune cells modification during cortical spreading depression in migraine was demonstrated, along with the existence and function of the glymphatic system. The better comprehension of the immune system abnormalities allowed the development of new immunomodulating drugs: the monoclonal antibodies against the CGRP or the CGRP receptor. Moreover, new insights into the molecular mechanism of CGRP, and the function of C-fibres and Aδ-fibres, highlighted the mechanism of action of Botulinum Toxin type A in the treatment of chronic migraine.

Oxytocin as a regulatory neuropeptide in the trigeminovascular system: Localization, expression and function of oxytocin and oxytocin receptors

Cephalalgia ◽  
2020 ◽  
Vol 40 (12) ◽  
pp. 1283-1295
Author(s):  
Karin Warfvinge ◽  
Diana N Krause ◽  
Aida Maddahi ◽  
Anne-Sofie Grell ◽  
Jacob CA Edvinsson ◽  
...  
Keyword(s):  
Dura Mater ◽  
Calcitonin Gene Related Peptide ◽  
Trigeminal Ganglia ◽  
Trigeminal Nucleus ◽  
Trigeminovascular System ◽  
Related Peptide ◽  
Oxytocin Receptors ◽  
Calcitonin Gene ◽  
And Function ◽  
Cranial Arteries

Background Recent clinical findings suggest that oxytocin could be a novel treatment for migraine. However, little is known about the role of this neuropeptide/hormone and its receptor in the trigeminovascular pathway. Here we determine expression, localization, and function of oxytocin and oxytocin receptors in rat trigeminal ganglia and targets of peripheral (dura mater and cranial arteries) and central (trigeminal nucleus caudalis) afferents. Methods The methods include immunohistochemistry, messenger RNA measurements, quantitative PCR, release of calcitonin gene-related peptide and myography of arterial segments. Results Oxytocin receptor mRNA was expressed in rat trigeminal ganglia and the receptor protein was localized in numerous small to medium-sized neurons and thick axons characteristic of A∂ sensory fibers. Double immunohistochemistry revealed only a small number of neurons expressing both oxytocin receptors and calcitonin gene-related peptide. In contrast, double immunostaining showed expression of the calcitonin gene-related peptide receptor component receptor activity-modifying protein 1 and oxytocin receptors in 23% of the small cells and in 47% of the medium-sized cells. Oxytocin immunofluorescence was observed only in trigeminal ganglia satellite glial cells. Oxytocin mRNA was below detection limit in the trigeminal ganglia. The trigeminal nucleus caudalis expressed mRNA for both oxytocin and its receptor. K+-evoked calcitonin gene-related peptide release from either isolated trigeminal ganglia or dura mater and it was not significantly affected by oxytocin (10 µM). Oxytocin directly constricted cranial arteries ex vivo (pEC50 ∼ 7); however, these effects were inhibited by the vasopressin V1A antagonist SR49059. Conclusion Oxytocin receptors are extensively expressed throughout the rat trigeminovascular system and in particular in trigeminal ganglia A∂ neurons and fibers, but no functional oxytocin receptors were demonstrated in the dura and cranial arteries. Thus, circulating oxytocin may act on oxytocin receptors in the trigeminal ganglia to affect nociception transmission. These effects may help explain hormonal influences in migraine and offer a novel way for treatment.

scholarly journals Alterations in PACAP-38-like immunoreactivity in the plasma during ictal and interictal periods of migraine patients

Cephalalgia ◽  
2013 ◽  
Vol 33 (13) ◽  
pp. 1085-1095 ◽  
Author(s):  
Bernadett Tuka ◽  
Zsuzsanna Helyes ◽  
Adrienn Markovics ◽  
Teréz Bagoly ◽  
János Szolcsányi ◽  
...  
Keyword(s):  
Adenylate Cyclase ◽  
Healthy Subjects ◽  
Disease Duration ◽  
Animal Experiments ◽  
Control Group ◽  
Trigeminovascular System ◽  
Blood Samples ◽  
Calcitonin Gene ◽  
Pituitary Adenylate Cyclase ◽  
Healthy Control

Background Recent studies on migraineurs and our own animal experiments have revealed that pituitary adenylate cyclase-activating polypeptide-38 (PACAP-38) has an important role in activation of the trigeminovascular system. The aim of this study was to determine the PACAP-38-like immunoreactivity (LI) in the plasma of healthy subjects, and parallel with the calcitonin gene-related peptide (CGRP)-LI in migraine patients in the ictal and interictal periods. Methods A total of 87 migraineurs and 40 healthy control volunteers were enrolled in the examination. Blood samples were collected from the cubital veins in both periods in 21 patients, and in either the ictal or the interictal period in the remaining 66 patients, and were analysed by radioimmunoassay. Results A significantly lower PACAP-38-LI was measured in the interictal plasma of the migraineurs as compared with the healthy control group ( p < 0.011). In contrast, elevated peptide levels were detected in the ictal period relative to the attack-free period in the 21 migraineurs ( pPACAP-38 < 0.001; pCGRP < 0.035) and PACAP-38-LI in the overall population of migraineurs ( p < 0.009). A negative correlation was observed between the interictal PACAP-38-LI and the disease duration. Conclusion This is the first study that has provided evidence of a clear association between migraine phases (ictal and interictal) and plasma PACAP-38-LI alterations.

scholarly journals Neuropeptide changes in an improved migraine model with repeat stimulations

2021 ◽  
Vol 12 (1) ◽  
pp. 523-532
Author(s):  
Yichen Guo ◽  
Yawen Cheng ◽  
Jiaqi An ◽  
Yi Qi ◽  
Guogang Luo
Keyword(s):  
Rat Model ◽  
Medical Condition ◽  
Future Research ◽  
Trigeminal Ganglia ◽  
Trigeminovascular System ◽  
Dynamic Changes ◽  
Repeated Stimulation ◽  
Calcitonin Gene ◽  
Pituitary Adenylate Cyclase ◽  
Stimulation Of

Abstract Migraine is a medical condition with a severe recursive headache. The activation of the trigeminovascular system is an important mechanism. The neuropeptide calcitonin gene-related peptide (CGRP) plays a crucial role in the pathogenesis of migraine. Several other neuropeptides are also involved; however, their roles in migraine remain unclear. In this study, using a rat model of migraine induced by electrical stimulation of the trigeminal ganglia (TG) and an improved version induced with repeated stimulation, we observed the dynamic changes of these peptides in TG and blood. We demonstrated that the expression of CGRP, pituitary adenylate cyclase activating polypeptide (PACAP), neuropeptide Y (NPY), vasoactive intestinal peptide, and nociceptin in TG was significantly elevated and peaked at different time points after a single stimulation. Their levels in the blood plasma were significantly increased at 12 h after stimulation. The peptides were further elevated with repeated stimulation. The improved rat model of migraine with repeated stimulation of TG resulted in a more pronounced elevation of CGRP, PACAP, and NPY. Thus, the dynamic changes in neuropeptides after stimulation suggest that these neuropeptides may play an important role in the pathogenesis of migraine. Additionally, the migraine model with repetitive stimulation would be a novel model for future research.

The mechanisms of action of Botulinum Toxin type A in nociceptive and neuropathic pathways in Cancer Pain.

2020 ◽  
Vol 27 ◽  
Author(s):  
Samuel Reyes-Long ◽  
Alfonso Alfaro-Rodríguez ◽  
Jose Luis Cortes-Altamirano ◽  
Eleazar LaraPadilla ◽  
Elizabeth Herrera-Maria ◽  
...  
Keyword(s):  
Botulinum Toxin ◽  
Pain Treatment ◽  
Botulinum Toxin Type A ◽  
Type A ◽  
Botulinum Toxin Type ◽  
Mechanisms Of Action ◽  
Nociceptive Transmission ◽  
Calcitonin Gene ◽  
Release Of Acetylcholine ◽  
Cancer Experience

Background: Botulinum toxin type A (BoNT-A) is widely employed for cosmetic purposes and in the treatment of certain diseases such as strabismus, hemifacial spasm and focal dystonia among others. BoNT-A effect mainly acts at the muscular level by inhibiting the release of acetylcholine at presynaptic levels consequently blocking the action potential in the neuromuscular junction. Despite the great progress in approval and pharmaceutical usage, improvement in displacing BoNT-A to other pathologies has remained short. Patients under diagnosis of several types of cancer experience pain in a myriad of ways; it can be experienced as hyperalgesia or allodynia, and the severity of the pain depends, in some degree, on the place that the tumor is located. Pain relief in patients diagnosed with cancer is not always optimal, and as the disease progresses, transition to more aggressive drugs, like opioids is sometimes unavoidable. In recent years BoNT-A employment in cancer has been explored, as well as an antinociceptive drug; experiments in neuropathic, inflammatory and acute pain have been carried out in animal models and humans. Although its mechanism has not been fully cleared evidence has shown that BoNT-A inhibits the secretion of pain mediators (substance P, Glutamate, and calcitonin gene related protein) from the nerve endings and dorsal root ganglion, impacting directly on the nociceptive transmission through the anterolateral and trigeminothalamic systems. Aim: Collect available literature regarding molecular, physiological and neurobiological evidence of the BoNT-A in cancer patients suffering from acute, neuropathic and inflammatory pain in order to identify possible mechanisms of action in which the BoNT-A could impact positively in pain treatment. Conclusion: BoNT-A could be an important neo-adjuvant and coadjuvant in the treatment of several types of cancer, diminish pro-tumor activity and secondary pain.

scholarly journals Neurovascular mechanisms of migraine and cluster headache

2017 ◽  
Vol 39 (4) ◽  
pp. 573-594 ◽  
Author(s):  
Jan Hoffmann ◽  
Serapio M Baca ◽  
Simon Akerman
Keyword(s):  
Cluster Headache ◽  
Vascular Response ◽  
Trigeminovascular System ◽  
The Past ◽  
Anatomical Basis ◽  
Calcitonin Gene ◽  
Pituitary Adenylate Cyclase ◽  
Acute Attacks ◽  
Trigeminal Activation

Vascular theories of migraine and cluster headache have dominated for many years the pathobiological concept of these disorders. This view is supported by observations that trigeminal activation induces a vascular response and that several vasodilating molecules trigger acute attacks of migraine and cluster headache in susceptible individuals. Over the past 30 years, this rationale has been questioned as it became clear that the actions of some of these molecules, in particular, calcitonin gene-related peptide and pituitary adenylate cyclase-activating peptide, extend far beyond the vasoactive effects, as they possess the ability to modulate nociceptive neuronal activity in several key regions of the trigeminovascular system. These findings have shifted our understanding of these disorders to a primarily neuronal origin with the vascular manifestations being the consequence rather than the origin of trigeminal activation. Nevertheless, the neurovascular component, or coupling, seems to be far more complex than initially thought, being involved in several accompanying features. The review will discuss in detail the anatomical basis and the functional role of the neurovascular mechanisms relevant to migraine and cluster headache.

scholarly journals Enxaqueca Crónica e Refratária: Como Diagnosticar e Tratar

2020 ◽  
Vol 33 (11) ◽  
pp. 753
Author(s):  
Elsa Parreira ◽  
Isabel Luzeiro ◽  
José Maria Pereira Monteiro
Keyword(s):  
Chronic Migraine ◽  
Medication Overuse Headache ◽  
Botulinum Toxin Type A ◽  
Botulinum Toxin Type ◽  
Migraine Treatment ◽  
The Novel ◽  
Personal Impact ◽  
Calcitonin Gene ◽  
Migraine Pathogenesis ◽  
Refractory Migraine

Migraine is highly prevalent and carries a significant personal, social and economic burden. It is the second cause of disability (years living with disability) worldwide and the first cause under 50 years of age. Chronic migraine (occurring for more than 15 days a month) and refractory migraine (treatment resistant), especially when there is also analgesic overuse, are the most disabling forms of migraine. These three disorders (chronic migraine, refractory migraine and medication overuse headache) are particularly difficult to treat. This article reviews their epidemiology, clinical presentation, diagnostic criteria, risk factors, comorbidities and social and personal impact. The therapeutic options available are discussed and focused on a multidisciplinary approach, non-pharmacological interventions treatment of comorbidities and avoiding analgesic overuse. Prophylactic treatments are mandatory and include the oral prophylactic treatments (topiramate), botulinum toxin type A and the novel monoclonal antibodies against calcitonin gene related peptide or its receptor, which are the first migraine preventive medicines developed specifically to target migraine pathogenesis. In refractory cases, multiple therapies are required including neurostimulation.

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