Differences in pituitary adenylate cyclase-activating peptide and calcitonin gene-related peptide release in the trigeminovascular system

Cephalalgia ◽  
2020 ◽  
Vol 40 (12) ◽  
pp. 1296-1309 ◽  
Author(s):  
Jacob Carl Alexander Edvinsson ◽  
Anne-Sofie Grell ◽  
Karin Warfvinge ◽  
Majid Sheykhzade ◽  
Lars Edvinsson ◽  
...  
Keyword(s):  
Adenylate Cyclase ◽  
Trigeminal Ganglion ◽  
Calcitonin Gene Related Peptide ◽  
Receptor Subtype ◽  
Primary Headaches ◽  
Satellite Glial Cells ◽  
Related Peptide ◽  
Calcitonin Gene ◽  
Pituitary Adenylate Cyclase ◽  
Peptide Release

Background Several neurotransmitters are expressed in the neurons of the trigeminal ganglion. One such signalling molecule is the pituitary adenylate cyclase-activating peptide (PACAP). PACAP signalling has been suggested to have a possible role in the pathophysiology of primary headaches. Objective The present study was designed to investigate the relationship between PACAP and calcitonin gene-related peptide, currently the two most relevant migraine peptides. Methods In the current study, we used ELISA to investigate PACAP and calcitonin gene-related peptide release in response to 60 mM K+ or capsaicin using a rat hemi-skull model. We combined this analysis with qPCR and immunohistochemistry to study the expression of PACAP and calcitonin gene-related peptide receptors and ligands. Results Calcitonin gene-related peptide (CGRP) is released from the trigeminal ganglion and dura mater. In contrast, PACAP is only released from the trigeminal ganglion. We observed a weak correlation between the stimulated release of the two neuropeptides. PACAP-38 immunoreactivity was expressed alone and in a subpopulation of neurons in the trigeminal ganglion that also store calcitonin gene-related peptide. The receptor subtype PAC1 was mainly expressed in the satellite glial cells (SGCs), which envelop the neurons in the trigeminal ganglion, in some neuronal processes, inside the Aδ-fibres and in the outermost layer of the myelin sheath that envelopes the Aδ-fibres. Conclusion Unlike CGRP, PACAP is only released within the trigeminal ganglion. This raises the question of whether a migraine therapy aimed at preventing peripheral PACAP signalling would be as successful as the CGRP signalling targeted treatments.

scholarly journals Current understanding of trigeminal ganglion structure and function in headache

Cephalalgia ◽  
2018 ◽  
Vol 39 (13) ◽  
pp. 1661-1674 ◽  
Author(s):  
Karl Messlinger ◽  
Andrew F Russo
Keyword(s):  
Glial Cells ◽  
Trigeminal Ganglion ◽  
Ganglion Cells ◽  
Sensory Information ◽  
Calcitonin Gene Related Peptide ◽  
Primary Headaches ◽  
Satellite Glial Cells ◽  
Related Peptide ◽  
Signaling Mechanisms ◽  
Calcitonin Gene

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.

Neuropeptide Regulation of Interleukin-6 Production from the Pituitary: Stimulation by Pituitary Adenylate Cyclase Activating Polypeptide and Calcitonin Gene-Related Peptide*

Endocrinology ◽  
1991 ◽  
Vol 129 (4) ◽  
pp. 1797-1804 ◽  
Author(s):  
ICHIRO TATSUNO ◽  
ANIKO SOMOGYVARI-VIGH ◽  
KEIKO MIZUNO ◽  
PAUL E. GOTTSCHALL ◽  
HIROYOSHI HIDAKA ◽  
...  
Keyword(s):  
Adenylate Cyclase ◽  
Interleukin 6 ◽  
Calcitonin Gene Related Peptide ◽  
Related Peptide ◽  
Calcitonin Gene ◽  
Pituitary Adenylate Cyclase

Les avancées dans les traitements de crise et de fond de la maladie migraineuse

2019 ◽  
Vol 213 (1-2) ◽  
pp. 59-64 ◽  
Author(s):  
Dominique Valade
Keyword(s):  
Ion Channels ◽  
Adenylate Cyclase ◽  
Phase I ◽  
Neuropeptide Y ◽  
Calcitonin Gene Related Peptide ◽  
Related Peptide ◽  
Acid Sensing Ion Channels ◽  
Calcitonin Gene ◽  
Pituitary Adenylate Cyclase ◽  
Anticorps Monoclonaux

Le traitement de la crise migraineuse repose actuellement sur les anti-inflammatoires non stéroïdiens (AINS) et les triptans, qui sont les deux seules classes pharmacologiques dont l’efficacité thérapeutique a été démontrée avec un haut niveau de preuve dans cette indication. Ces deux classes pharmacologiques ne couvrent cependant pas tous les besoins thérapeutiques des migraineux. Deux programmes de développement clinique méritent une attention particulière et concernent les antagonistes des récepteurs du CGRP et les agonistes du récepteur 5-HT1F de la sérotonine. L’approche prophylactique est un élément capital du traitement de la migraine épisodique qui concerne plus d’un tiers des migraineux. Actuellement, cette approche prophylactique est possible au travers de plusieurs traitements pharmacologiques ayant un bon niveau de preuve dans cette indication et appartenant à diverses classes pharmacologiques : bêta-bloquants (propranolol, métoprolol), antiépileptiques (divalproate de sodium, topiramate, gabapentine), inhibiteurs calciques (flunarizine), antidépresseurs tricycliques et antagonistes sérotoninergiques (pizotifène). L’approche prophylactique peut également faire appel en seconde intention à des molécules mises plus récemment sur le marché mais dont le niveau de preuve dans cette indication est plus faible : vérapamil, venlafaxine, lisinopril et candesartan. Enfin, il convient de ne pas oublier l’utilisation d’anciens traitements (oxétorone) toujours en usage dans certains pays (comme la France). Devant le manque de spécificité, de nouveaux médicaments émergent, les plus importants étant les anticorps monoclonaux antagonistes du Calcitonin Gene-Related Peptide (CGRP), mais de nombreux autres sont en phase I ou II de recherche tels que les modulateurs de la fonction endothéliale, les antagonistes orexinergiques, l’ocytocine, les inhibiteurs non sélectifs des phosphodiestérases, les modulateurs des jonctions communicantes. Enfin, un futur plus lointain repose sur les neuropeptides hypothalamiques (Pituitary Adenylate Cyclase-Activating Polypeptide, PACAP ; neuropeptide Y, NPY), les inhibiteurs de synthèse de l’oxyde nitrique (NO) et les canaux ioniques activés par l’acidité extracellulaire (ASIC, Acid-Sensing Ion Channels).

Oxytocin receptor: Expression in the trigeminal nociceptive system and potential role in the treatment of headache disorders

Cephalalgia ◽  
2016 ◽  
Vol 36 (10) ◽  
pp. 943-950 ◽  
Author(s):  
Alexander Tzabazis ◽  
Jordan Mechanic ◽  
James Miller ◽  
Michael Klukinov ◽  
Conrado Pascual ◽  
...  
Keyword(s):  
Trigeminal Ganglion ◽  
Calcitonin Gene Related Peptide ◽  
Oxytocin Receptor ◽  
Receptor Expression ◽  
Electrocutaneous Stimulation ◽  
Related Peptide ◽  
Calcitonin Gene ◽  
Peptide Release ◽  
Trigeminal Ganglion Neurons ◽  
Ganglion Neurons

Aims Our studies investigated the location of oxytocin receptors in the peripheral trigeminal sensory system and determined their role in trigeminal pain. Methods Oxytocin receptor expression and co-localization with calcitonin gene-related peptide was investigated in rat trigeminal ganglion using immunohistochemistry. Enzyme-linked immunosorbent assay was used to determine the effects of facial electrocutaneous stimulation and adjuvant-induced inflammation of the temporomandibular joint on oxytocin receptor expression in the trigeminal ganglion. Finally, the effects of oxytocin on capsaicin-induced calcitonin gene-related peptide release from dural nociceptors were investigated using isolated rat dura mater. Results Oxytocin receptor immunoreactivity was present in rat trigeminal neurons. The vast majority of oxytocin receptor immunoreactive neurons co-expressed calcitonin gene-related peptide. Both electrocutaneous stimulation and adjuvant-induced inflammation led to a rapid upregulation of oxytocin receptor protein expression in trigeminal ganglion neurons. Oxytocin significantly and dose-dependently decreased capsaicin-induced calcitonin gene-related peptide release from dural nociceptors. Conclusion Oxytocin receptor expression in calcitonin gene-related peptide containing trigeminal ganglion neurons, and the blockade of calcitonin gene-related peptide release from trigeminal dural afferents suggests that activation of these receptors may provide therapeutic benefit in patients with migraine and other primary headache disorders.

Exploration of purinergic receptors as potential anti-migraine targets using established pre-clinical migraine models

Cephalalgia ◽  
2019 ◽  
Vol 39 (11) ◽  
pp. 1421-1434 ◽  
Author(s):  
Kristian A Haanes ◽  
Alejandro Labastida-Ramírez ◽  
Frank W Blixt ◽  
Eloisa Rubio-Beltrán ◽  
Clemens M Dirven ◽  
...  
Keyword(s):  
Trigeminal Ganglion ◽  
Purinergic Receptors ◽  
Middle Meningeal Artery ◽  
Calcitonin Gene Related Peptide ◽  
P2x3 Receptor ◽  
Related Peptide ◽  
Migraine Pain ◽  
Calcitonin Gene ◽  
Peptide Release ◽  
Meningeal Artery

Background The current understanding of mechanisms behind migraine pain has been greatly enhanced with the recent therapies targeting calcitonin gene-related peptide and its receptor. The clinical efficacy of calcitonin gene-related peptide-blocking drugs indicates that, at least in a considerable proportion of patients, calcitonin gene-related peptide is a key molecule in migraine pain. There are several receptors and molecular pathways that can affect the release of and response to calcitonin gene-related peptide. One of these could be purinergic receptors that are involved in nociception, but these are greatly understudied with respect to migraine. Objective We aimed to explore purinergic receptors as potential anti-migraine targets. Methods We used the human middle meningeal artery as a proxy for the trigeminal system to screen for possible anti-migraine candidates. The human findings were followed by intravital microscopy and calcitonin gene-related peptide release measurements in rodents. Results We show that the purinergic P2Y13 receptor fulfills all the features of a potential anti-migraine target. The P2Y13 receptor is expressed in both the human trigeminal ganglion and middle meningeal artery and activation of this receptor causes: a) middle meningeal artery contraction in vitro; b) reduced dural artery dilation following periarterial electrical stimulation in vivo and c) a reduction of CGRP release from both the dura and the trigeminal ganglion in situ. Furthermore, we show that P2X3 receptor activation of the trigeminal ganglion causes calcitonin gene-related peptide release and middle meningeal artery dilation. Conclusion Both an agonist directed at the P2Y13 receptor and an antagonist of the P2X3 receptor seem to be viable potential anti-migraine therapies.

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