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Headache May 2019The 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... (Review)
Review
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. Additionally, the potential exists that this therapeutic strategy may also alleviate cluster headache as well.
Topics: Animals; Calcitonin Gene-Related Peptide; Humans; Migraine Disorders; Neuroglia; Neurons; Nociception; Trigeminal Ganglion; Trigeminal Nerve
PubMed: 30982963
DOI: 10.1111/head.13529 -
Neuron Jun 2022Sensitization of trigeminal ganglion neurons contributes to primary headache disorders such as migraine, but the specific neuronal and non-neuronal trigeminal subtypes...
Sensitization of trigeminal ganglion neurons contributes to primary headache disorders such as migraine, but the specific neuronal and non-neuronal trigeminal subtypes that are involved remain unclear. We thus developed a cell atlas in which human and mouse trigeminal ganglia are transcriptionally and epigenomically profiled at single-cell resolution. These data describe evolutionarily conserved and human-specific gene expression patterns within each trigeminal ganglion cell type, as well as the transcription factors and gene regulatory elements that contribute to cell-type-specific gene expression. We then leveraged these data to identify trigeminal ganglion cell types that are implicated both by human genetic variation associated with migraine and two mouse models of headache. This trigeminal ganglion cell atlas improves our understanding of the cell types, genes, and epigenomic features involved in headache pathophysiology and establishes a rich resource of cell-type-specific molecular features to guide the development of more selective treatments for headache and facial pain.
Topics: Animals; Disease Models, Animal; Headache; Humans; Mice; Migraine Disorders; Neurons; Trigeminal Ganglion
PubMed: 35349784
DOI: 10.1016/j.neuron.2022.03.003 -
The Journal of Headache and Pain Jun 2020Migraine is a leading cause of disability worldwide, but it is still underdiagnosed and undertreated. Research on the pathophysiology of this neurological disease led to... (Review)
Review
Migraine is a leading cause of disability worldwide, but it is still underdiagnosed and undertreated. Research on the pathophysiology of this neurological disease led to the discovery that calcitonin gene-related peptide (CGRP) is a key neuropeptide involved in pain signaling during a migraine attack. CGRP-mediated neuronal sensitization and glutamate-based second- and third-order neuronal signaling may be an important component involved in migraine pain. The activation of several serotonergic receptor subtypes can block the release of CGRP, other neuropeptides, and neurotransmitters, and can relieve the symptoms of migraine. Triptans were the first therapeutics developed for the treatment of migraine, working through serotonin 5-HT receptors. The discovery that the serotonin 1F (5-HT) receptor was expressed in the human trigeminal ganglion suggested that this receptor subtype may have a role in the treatment of migraine. The 5-HT receptor is found on terminals and cell bodies of trigeminal ganglion neurons and can modulate the release of CGRP from these nerves. Unlike 5-HT receptors, the activation of 5-HT receptors does not cause vasoconstriction.The potency of different serotonergic agonists towards 5-HT was correlated in an animal model of migraine (dural plasma protein extravasation model) leading to the development of lasmiditan. Lasmiditan is a newly approved acute treatment for migraine in the United States and is a lipophilic, highly selective 5-HT agonist that can cross the blood-brain barrier and act at peripheral nervous system (PNS) and central nervous system (CNS) sites.Lasmiditan activation of CNS-located 5-HT receptors (e.g., in the trigeminal nucleus caudalis) could potentially block the release of CGRP and the neurotransmitter glutamate, thus preventing and possibly reversing the development of central sensitization. Activation of 5-HT receptors in the thalamus can block secondary central sensitization of this region, which is associated with progression of migraine and extracephalic cutaneous allodynia. The 5-HT receptors are also elements of descending pain modulation, presenting another site where lasmiditan may alleviate migraine. There is emerging evidence that mitochondrial dysfunction might be implicated in the pathophysiology of migraine, and that 5-HT receptors can promote mitochondrial biogenesis. While the exact mechanism is unknown, evidence suggests that lasmiditan can alleviate migraine through 5-HT agonist activity that leads to inhibition of neuropeptide and neurotransmitter release and inhibition of PNS trigeminovascular and CNS pain signaling pathways.
Topics: Animals; Benzamides; Calcitonin Gene-Related Peptide; Humans; Migraine Disorders; Neurons; Piperidines; Pyridines; Receptors, Serotonin; Serotonin Receptor Agonists; Trigeminal Ganglion; Tryptamines; Vasoconstriction; Receptor, Serotonin, 5-HT1F
PubMed: 32522164
DOI: 10.1186/s10194-020-01132-3 -
Journal of Neural Transmission (Vienna,... Apr 2020The trigeminal ganglion with its three trigeminal nerve tracts consists mainly of clusters of sensory neurons with their peripheral and central processes. Most neurons... (Review)
Review
The trigeminal ganglion with its three trigeminal nerve tracts consists mainly of clusters of sensory neurons with their peripheral and central processes. Most neurons are surrounded by satellite glial cells and the axons are wrapped by myelinating and non-myelinating Schwann cells. Trigeminal neurons express various neuropeptides, most notably, calcitonin gene-related peptide (CGRP), substance P, and pituitary adenylate cyclase-activating polypeptide (PACAP). Two types of CGRP receptors are expressed in neurons and satellite glia. A variety of other signal molecules like ATP, nitric oxide, cytokines, and neurotrophic factors are released from trigeminal ganglion neurons and signal to neighboring neurons or satellite glial cells, which can signal back to neurons with same or other mediators. This potential cross-talk of signals involves intracellular mechanisms, including gene expression, that can modulate mediators of sensory information, such as neuropeptides, receptors, and neurotrophic factors. From the ganglia cell bodies, which are outside the blood-brain barrier, the mediators are further distributed to peripheral sites and/or to the spinal trigeminal nucleus in the brainstem, where they can affect neural transmission. A major question is how the sensory neurons in the trigeminal ganglion differ from those in the dorsal root ganglion. Despite their functional overlap, there are distinct differences in their ontogeny, gene expression, signaling pathways, and responses to anti-migraine drugs. Consequently, drugs that modulate cross-talk in the trigeminal ganglion can modulate both peripheral and central sensitization, which may potentially be distinct from sensitization mediated in the dorsal root ganglion.
Topics: Animals; Ganglia, Spinal; Humans; Neurons, Afferent; Neuropeptides; Nociception; Signal Transduction; Trigeminal Ganglion
PubMed: 32088764
DOI: 10.1007/s00702-020-02161-7 -
Cephalalgia : An International Journal... Nov 2019The trigeminal ganglion is unique among the somatosensory ganglia regarding its topography, structure, composition and possibly some functional properties of its... (Review)
Review
INTRODUCTION
The trigeminal ganglion is unique among the somatosensory ganglia regarding its topography, structure, composition and possibly some functional properties of its cellular components. Being mainly responsible for the sensory innervation of the anterior regions of the head, it is a major target for headache research. One intriguing question is if the trigeminal ganglion is merely a transition site for sensory information from the periphery to the central nervous system, or if intracellular modulatory mechanisms and intercellular signaling are capable of controlling sensory information relevant for the pathophysiology of headaches.
METHODS
An online search based on PubMed was made using the keyword "trigeminal ganglion" in combination with "anatomy", "headache", "migraine", "neuropeptides", "receptors" and "signaling". From the relevant literature, further references were selected in view of their relevance for headache mechanisms. The essential information was organized based on location and cell types of the trigeminal ganglion, neuropeptides, receptors for signaling molecules, signaling mechanisms, and their possible relevance for headache generation.
RESULTS
The trigeminal ganglion consists of clusters of sensory neurons and their peripheral and central axon processes, which are arranged according to the three trigeminal partitions V1-V3. The neurons are surrounded by satellite glial cells, the axons by Schwann cells. In addition, macrophage-like cells can be found in the trigeminal ganglion. Neurons express various neuropeptides, among which calcitonin gene-related peptide is the most prominent in terms of its prevalence and its role in primary headaches. The classical calcitonin gene-related peptide receptors are expressed in non-calcitonin gene-related peptide neurons and satellite glial cells, although the possibility of a second calcitonin gene-related peptide receptor in calcitonin gene-related peptide neurons remains to be investigated. A variety of other signal molecules like adenosine triphosphate, nitric oxide, cytokines, and neurotrophic factors are released from trigeminal ganglion cells and may act at receptors on adjacent neurons or satellite glial cells.
CONCLUSIONS
The trigeminal ganglion may act as an integrative organ. The morphological and functional arrangement of trigeminal ganglion cells suggests that intercellular and possibly also autocrine signaling mechanisms interact with intracellular mechanisms, including gene expression, to modulate sensory information. Receptors and neurotrophic factors delivered to the periphery or the trigeminal brainstem can contribute to peripheral and central sensitization, as in the case of primary headaches. The trigeminal ganglion as a target of drug action outside the blood-brain barrier should therefore be taken into account.
Topics: Adenosine Triphosphate; Afferent Pathways; Animals; Calcitonin Gene-Related Peptide; Calcitonin Gene-Related Peptide Receptor Antagonists; Cytokines; Headache; Humans; Intercellular Signaling Peptides and Proteins; Migraine Disorders; Nerve Growth Factors; Neuropeptides; Nitric Oxide; Nociception; Rats; Receptors, Calcitonin Gene-Related Peptide; Receptors, Neuropeptide; Sensory Receptor Cells; Signal Transduction; Trigeminal Ganglion
PubMed: 29989427
DOI: 10.1177/0333102418786261 -
The Journal of Headache and Pain Nov 2022Excruciating trigeminal neuralgia (TN) management is very difficult and severely affects the patient's quality of life. Earlier studies have shown that the trigeminal... (Review)
Review
Excruciating trigeminal neuralgia (TN) management is very difficult and severely affects the patient's quality of life. Earlier studies have shown that the trigeminal ganglion (TG) comprises several receptors and signal molecules that are involved in the process of peripheral sensitization, which influences the development and persistence of neuropathic pain. Targeting TG can modulate this sensitization pathway and mediate the pain-relieving effect. So far,there are few studies in which modulation approaches to TG itself have been suggested so far. "Trigeminal ganglion modulation" and "trigeminal neuralgia" were used as search phrases in the Scopus Index and PubMed databases to discover articles that were pertinent to the topic. In this review, we address the role of the trigeminal ganglion in TN and underlying molecules and neuropeptides implicated in trigeminal pain pathways in processing pathological orofacial pain. We also reviewed different modulation approaches in TG for TN management. Furthermore, we discuss the prospect of targeting trigeminal ganglion to manage such intractable pain.
Topics: Humans; Trigeminal Ganglion; Quality of Life; Trigeminal Neuralgia; Neuralgia; Facial Pain
PubMed: 36424545
DOI: 10.1186/s10194-022-01512-x -
Neuroscience Jan 2018A fundamental question in the investigation of any sensory system is what physical signals drive its sensory neurons during natural behavior. Surprisingly, in the... (Review)
Review
A fundamental question in the investigation of any sensory system is what physical signals drive its sensory neurons during natural behavior. Surprisingly, in the whisker system, it is only recently that answers to this question have emerged. Here, we review the key developments, focussing mainly on the first stage of the ascending pathway - the primary whisker afferents (PWAs). We first consider a biomechanical framework, which describes the fundamental mechanical forces acting on the whiskers during active sensation. We then discuss technical progress that has allowed such mechanical variables to be estimated in awake, behaving animals. We discuss past electrophysiological evidence concerning how PWAs function and reinterpret it within the biomechanical framework. Finally, we consider recent studies of PWAs in awake, behaving animals and compare the results to related studies of the cortex. We argue that understanding 'what the whiskers tell the brain' sheds valuable light on the computational functions of downstream neural circuits, in particular, the barrel cortex.
Topics: Afferent Pathways; Animals; Biomechanical Phenomena; Somatosensory Cortex; Touch Perception; Trigeminal Ganglion; Vibrissae
PubMed: 28843998
DOI: 10.1016/j.neuroscience.2017.08.005 -
Experimental Eye Research Jun 2022Herpes Simplex Virus-1 (HSV-1) is a neurotropic virus that can infect humans in the eye and travel to the trigeminal ganglion to establish latency. HSV-1 causes various... (Review)
Review
Herpes Simplex Virus-1 (HSV-1) is a neurotropic virus that can infect humans in the eye and travel to the trigeminal ganglion to establish latency. HSV-1 causes various disease states in both the primary and secondary sites of infection including the eye and the nervous system. This DNA virus exploits various adaptive measures to infect host cells, hijack host cell proteins, evade host immune response and spread from cell-to-cell to avoid immune detection. Recent data suggest that Optineurin (OPTN), a host protein, is a key restriction factor that prevents cell-to-cell spread of HSV-1 and guards against serious damage to the nervous system during infection. In recent years OPTN has gained increased attention because of its involvement in cellular mechanisms that promote homeostasis and prevent neurodegeneration. At the center of it all is the role OPTN plays as a receptor for selective autophagy. This review summarizes our latest understanding of the viral lifecycle, disease pathologies, and OPTN-mediated protective mechanisms during HSV-1 infection of the eye and the nervous system. We specifically highlight recent discoveries that implicate OPTN as crucial in the prevention of ocular and neurodegenerative diseases.
Topics: Eye Infections; Herpes Simplex; Herpesvirus 1, Human; Humans; Keratitis, Herpetic; Trigeminal Ganglion
PubMed: 35390332
DOI: 10.1016/j.exer.2022.109059 -
The Journal of Headache and Pain Jun 2020The fifth cranial nerve is the common denominator for many headaches and facial pain pathologies currently known. Projecting from the trigeminal ganglion, in a bipolar... (Review)
Review
The fifth cranial nerve is the common denominator for many headaches and facial pain pathologies currently known. Projecting from the trigeminal ganglion, in a bipolar manner, it connects to the brainstem and supplies various parts of the head and face with sensory innervation. In this review, we describe the neuroanatomical structures and pathways implicated in the sensation of the trigeminal system. Furthermore, we present the current understanding of several primary headaches, painful neuropathies and their pharmacological treatments. We hope that this overview can elucidate the complex field of headache pathologies, and their link to the trigeminal nerve, to a broader field of young scientists.
Topics: Animals; Brain Stem; Facial Pain; Headache; Humans; Trigeminal Ganglion; Trigeminal Nerve
PubMed: 32503421
DOI: 10.1186/s10194-020-01134-1 -
Neuroscience Bulletin Apr 2021Trigeminal neuropathic pain (TNP) is a significant health problem but the involved mechanism has not been completely elucidated. Toll-like receptors (TLRs) have recently...
Trigeminal neuropathic pain (TNP) is a significant health problem but the involved mechanism has not been completely elucidated. Toll-like receptors (TLRs) have recently been demonstrated to be expressed in the dorsal root ganglion and involved in chronic pain. Here, we show that TLR8 was persistently increased in the trigeminal ganglion (TG) neurons in model of TNP induced by partial infraorbital nerve ligation (pIONL). In addition, deletion or knockdown of Tlr8 in the TG attenuated pIONL-induced mechanical allodynia, reduced the activation of ERK and p38-MAPK, and decreased the expression of pro-inflammatory cytokines in the TG. Furthermore, intra-TG injection of the TLR8 agonist VTX-2337 induced pain hypersensitivity. VTX-2337 also increased the intracellular Ca concentration, induced the activation of ERK and p38, and increased the expression of pro-inflammatory cytokines in the TG. These data indicate that TLR8 contributes to the maintenance of TNP through increasing MAPK-mediated neuroinflammation. Targeting TLR8 signaling may be effective for the treatment of TNP.
Topics: Animals; Hyperalgesia; Mice; Neuralgia; Toll-Like Receptor 8; Trigeminal Ganglion; Trigeminal Neuralgia
PubMed: 33355900
DOI: 10.1007/s12264-020-00621-4