Diverse Physiological Roles of Calcitonin Gene-Related Peptide in Migraine Pathology: Modulation of Neuronal-Glial-Immune Cells to Promote Peripheral and Central Sensitization

Durham, Paul L.

doi:10.1007/s11916-016-0578-4

Cited by 50 publications

(51 citation statements)

References 100 publications

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“…Moreover, TNF‐α can acutely sensitize TG neurons directly, as well as evoke the upregulation of several proinflammatory cytokines in these neurons, likely through the TNF‐α receptors . Together, these studies demonstrate that CGRP secreted from TG neurons can increase cytokine production in TG neurons and satellite glial cells and increase its own production and release from neurons, maintaining a sensitized state and enhancing pain …”

Section: Role Of Trigeminal Cgrp In Migraine – Preclinical Evidencementioning

confidence: 99%

“…129 Together, these studies demonstrate that CGRP secreted from TG neurons can increase cytokine production in TG neurons and satellite glial cells and increase its own production and release from neurons, maintaining a sensitized state and enhancing pain. 124,126,129,130 Central CGRP in Migraine.-As discussed in several recent reviews, it is generally accepted that anti-CGRP therapeutics most likely act peripherally to relieve migraine attacks, since the small-molecule CGRP receptor antagonists and the anti-CGRP antibodies have very little ability to cross the blood-brain barrier. 9,108,[131][132][133][134][135] Nonetheless, a central role of CGRP in migraine is still possible, since several studies reveal a widespread distribution of the neuropeptide and the receptor components CLR and RAMP1 throughout the CNS.…”

Section: Role Of Trigeminal Cgrp In Migraine -Preclinical Evidencementioning

confidence: 99%

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CGRP and the Trigeminal System in Migraine

et al. 2019

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Objective The goal of this narrative review is to provide an overview of migraine pathophysiology, with an emphasis on the role of calcitonin gene‐related peptide (CGRP) within the context of the trigeminovascular system. Background Migraine is a prevalent and disabling neurological disease that is characterized in part by intense, throbbing, and unilateral headaches. Despite recent advances in understanding its pathophysiology, migraine still represents an unmet medical need, as it is often underrecognized and undertreated. Although CGRP has been known to play a pivotal role in migraine for the last 2 decades, this has now received more interest spurred by the early clinical successes of drugs that block CGRP signaling in the trigeminovascular system. Design This narrative review presents an update on the role of CGRP within the trigeminovascular system. PubMed searches were used to find recent (ie, 2016 to November 2018) published articles presenting new study results. Review articles are also included not as primary references but to bring these to the attention of the reader. Original research is referenced in describing the core of the narrative, and review articles are used to support ancillary points. Results The trigeminal ganglion neurons provide the connection between the periphery, stemming from the interface between the primary afferent fibers of the trigeminal ganglion and the meningeal vasculature and the central terminals in the trigeminal nucleus caudalis. The neuropeptide CGRP is abundant in trigeminal ganglion neurons, and is released from the peripheral nerve and central nerve terminals as well as being secreted within the trigeminal ganglion. Release of CGRP from the peripheral terminals initiates a cascade of events that include increased synthesis of nitric oxide and sensitization of the trigeminal nerves. Secreted CGRP in the trigeminal ganglion interacts with adjacent neurons and satellite glial cells to perpetuate peripheral sensitization, and can drive central sensitization of the second‐order neurons. A shift in central sensitization from activity‐dependent to activity‐independent central sensitization may indicate a mechanism driving the progression of episodic migraine to chronic migraine. The pathophysiology of cluster headache is much more obscure than that of migraine, but emerging evidence suggests that it may also involve hypersensitivity of the trigeminovascular system. Ongoing clinical studies with therapies targeted at CGRP will provide additional, valuable insights into the pathophysiology of this disorder. Conclusions CGRP plays an essential role in the pathophysiology of migraine. Treatments that interfere with the functioning of CGRP in the peripheral trigeminal system are effective against migraine. Blocking sensitization of the trigeminal nerve by attenuating CGRP activity in the periphery may be sufficient to block a migraine attack. Addit...

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Section: Role Of Trigeminal Cgrp In Migraine – Preclinical Evidencementioning

confidence: 99%

Section: Role Of Trigeminal Cgrp In Migraine -Preclinical Evidencementioning

confidence: 99%

CGRP and the Trigeminal System in Migraine

et al. 2019

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“…In particular, members of the mitogen-activated protein kinase (MAPK) family mediate intracellular signaling cascades that promote neuron-glia interactions and maintain a hyperexcitable state of nociceptive neurons (Crown, 2012; Ji et al, 2009; Ji et al, 2013). The neuropeptide calcitonin gene-related peptide (CGRP), whose expression is regulated by MAPK and is strongly implicated in migraine pathology, can promote sensitization of primary and secondary trigeminal nociceptive neurons and activation of satellite glial cells in the ganglion and astrocytes and microglia in the spinal cord (Durham, 2016; Iyengar et al, 2017; Seybold, 2009). …”

Section: Introductionmentioning

confidence: 99%

Secondary traumatic stress increases expression of proteins implicated in peripheral and central sensitization of trigeminal neurons

et al. 2018

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The pathology of migraine, a common neurological disease, involves sensitization and activation of trigeminal nociceptive neurons to promote hyperalgesia and allodynia during an attack. Migraineurs often exhibit characteristics of a hyperexcitable or hypervigilant nervous system. One of the primary reported risk factors for development of a hyperexcitable trigeminal system is chronic, unmanaged stress and anxiety. While primary traumatic stress is a commonly cited risk factor for many pain conditions, exposure to secondary traumatic stress early in life is also thought to be a contributing risk factor. The goal of this study was to investigate cellular changes within the spinal trigeminal nucleus and trigeminal ganglion mediated by secondary traumatic stress. Male Sprague Dawley rats (sender) were subjected to forced swim testing (primary traumatic stress) and were then housed in close visual, olfactory, and auditory proximity to the breeding male and female rats, pregnant female rats, or female rats and their nursing offspring (all receivers). In response to secondary stress, levels of calcitonin gene-related peptide, active forms of the mitogen activated protein kinases ERK, JNK, and p38, and astrocyte expression of glial fibrillary acidic protein were significantly elevated in the spinal trigeminal nucleus in day 45 offspring when compared to naïve offspring. In addition, increased nuclear expression of ERK and p38 was observed in trigeminal ganglion neurons. Our results demonstrate that secondary traumatic stress promotes cellular events associated with prolonged trigeminal sensitization in the offspring, and provides a mechanism of how early life stress may function as a risk factor for migraine.

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“…19 The activated afferents also release vasoactive peptides such as CGRP locally causing meningeal vasodilation and neurogenic inflammation, which may also contribute to some extent to the pain. 20 Hence, the neurogenic theory makes it clear that vasodilation occurs secondary to neuronal dysfunction and is not the primary cause of migraine pain.…”

Section: Migraine Pathophysiologymentioning

confidence: 99%

“…24 CGRP receptors have multiple components, which include the calcitonin receptor-like receptor (CLR), the receptor activity-modifying protein (RAMP), along with a receptor component protein (RCP). 20 CGRP receptors are highly expressed in the trigeminovascular system and have been demonstrated in various sites such as the cell body of neurons and satellite glial cells of the trigeminal ganglion, meningeal mast cells as well as in the meningeal vasculature. 25 CGRP and its receptor have also been demonstrated in the central nervous system in areas such as the trigeminal nucleus caudalis, brainstem nuclei periaqueductal grey, thalamus, hypothalamus and cerebellum.…”

Section: Involvement Of Cgrp In Migrainementioning

confidence: 99%

Anti‐CGRP monoclonal antibodies: breakthrough in migraine therapeutics

Krishnaswamy¹,

Malik²,

Khan³

et al. 2019

Prog Neurol Psychiatry

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Migraine is considered as one of the most debilitating neurological disorders but the success of the anti‐calcitonin gene‐related peptide (CGRP) therapies marks a new era in the treatment of migraine and has paved way for further research into the exact pathophysiology of migraine. Here, the authors discuss their literature review on the anti‐CGRP therapies to examine the pathophysiology of migraine, with a focus on the possible role of CGRP and the safety and efficacy of monoclonal antibodies targeting it.

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Diverse Physiological Roles of Calcitonin Gene-Related Peptide in Migraine Pathology: Modulation of Neuronal-Glial-Immune Cells to Promote Peripheral and Central Sensitization

Cited by 50 publications

References 100 publications

CGRP and the Trigeminal System in Migraine

CGRP and the Trigeminal System in Migraine

Secondary traumatic stress increases expression of proteins implicated in peripheral and central sensitization of trigeminal neurons

Anti‐CGRP monoclonal antibodies: breakthrough in migraine therapeutics

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