Circulating Nociceptin Levels During the Cluster Headache Period

Cephalalgia ◽  
2004 ◽  
Vol 24 (4) ◽  
pp. 280-283 ◽  
Author(s):  
C Ertsey ◽  
M Hantos ◽  
G Bozsik ◽  
K Tekes
Keyword(s):  
Cluster Headache ◽  
Trigeminal Ganglion ◽  
Ganglion Cells ◽  
Endogenous Ligand ◽  
Related Peptide ◽  
Calcitonin Gene ◽  
Site Of Action ◽  
Circulating Levels ◽  
Age And Sex ◽  
Headache Patients

The trigeminal innervation of the dura and its vessels has a prominent role in the mechanism of cluster headache. Nociceptin, an opioid neuropeptide, is the endogenous ligand of the OP-4 receptor, with both algesic and analgesic properties depending on the site of action. Nociceptin and its receptor are expressed by trigeminal ganglion cells where they co-localize with calcitonin gene-related peptide, a marker peptide of the trigeminovascular neurones. Nociceptin inhibits neurogenic dural vasodilatation, a phenomenon related to trigeminovascular activation. To explore its possible involvement in cluster headache, we studied circulating levels of nociceptin when attack-free during the cluster period, and also after the termination of the cluster period, using radioimmunoassay. In 14 cluster headache patients nociceptin levels during the cluster period were significantly lower than in age-, and sex-matched controls (4.91 ± 1.96 vs. 9.58 ± 2.57 pg/ml, P < 0.01). After the termination of the cluster period nociceptin levels (8.60 ± 1.47 pg/ml) were not statistically different from controls. Nociceptin levels did not correlate with age, length of disease or episode length. Lower nociceptin levels during the cluster period may result in a defective regulation of trigeminal activity that might not protect sufficiently against the attacks.

scholarly journals Effect of calcitonin gene-related peptide (-receptor) antibodies in chronic cluster headache: Results from a retrospective case series support individual treatment attempts

Cephalalgia ◽  
2020 ◽  
Vol 40 (14) ◽  
pp. 1574-1584 ◽  
Author(s):  
Ruth Ruscheweyh ◽  
Gregor Broessner ◽  
Gudrun Goßrau ◽  
Katja Heinze-Kuhn ◽  
Tim P Jürgens ◽  
...  
Keyword(s):  
Cluster Headache ◽  
Calcitonin Gene Related Peptide ◽  
Chronic Cluster Headache ◽  
Individual Treatment ◽  
Attack Frequency ◽  
Peptide Receptor ◽  
Related Peptide ◽  
Calcitonin Gene ◽  
Receptor Antibodies ◽  
Headache Patients

Objective To assess the efficacy of monoclonal antibodies targeting calcitonin gene-related peptide (CGRP) or its receptor in chronic cluster headache (CCH) treatment under real world conditions. Background Calcitonin gene-related peptide has an important pathophysiological role in cluster headache. Although the randomised controlled trial with the calcitonin gene-related peptide antibody galcanezumab was negative, chronic cluster headache patients with insufficient response to other preventive treatments have been receiving individual off-label treatment attempts with calcitonin gene-related peptide-(receptor) antibodies. Methods Data from 22 chronic cluster headache patients who received at least one dose of a calcitonin gene-related peptide(-receptor) antibody and recorded attack frequency in a headache diary were retrospectively collected at eight headache centres. Results The number of previous preventive therapies was 6.5 ± 2.4 (mean ± standard deviation, range: 2–11). The average number of attacks per week was 23.3 ± 16.4 at baseline and significantly decreased by −9.2 ± 9.7 in the first month of treatment with a calcitonin gene-related peptide(-receptor) antibody ( p < 0.001). Fifty-five percent of the patients were 50% responders and 36% were 75% responders with respect to attack frequency. Significant reduction of attack frequency started at week 1 (−6.8 ± 2.8 attacks, p < 0.01). Results were corroborated by significant decreases in weekly uses of acute headache medication (−9.8 ± 7.6, p < 0.001) and pain intensity during attacks (−1.2 ± 2.0, numerical rating scale (NRS) [0–10], p < 0.01) in the first month. In months 2 (n = 14) and 3 (n = 10), reduction of attack frequency from baseline was −8.0 ± 8.4 ( p = 0.004) and −9.1 ± 10.0 ( p = 0.024), respectively. Conclusion Under real-world conditions, individual treatment with calcitonin gene-related peptide(-receptor) antibodies was effective in 55% of our chronic cluster headache patients. This finding supports individual off-label treatment attempts with calcitonin gene-related peptide-(receptor) antibodies in chronic cluster headache patients insufficiently responding to other therapies.

scholarly journals Release of the predicted calcitonin gene-related peptide from cultured rat trigeminal ganglion cells

Nature ◽  
1984 ◽  
Vol 308 (5960) ◽  
pp. 653-655 ◽  
Author(s):  
R. Tom Mason ◽  
Robert A. Peterfreund ◽  
Paul E. Sawchenko ◽  
Anne Z. Corrigan ◽  
Jean E. Rivier ◽  
...  
Keyword(s):  
Trigeminal Ganglion ◽  
Ganglion Cells ◽  
Calcitonin Gene Related Peptide ◽  
Related Peptide ◽  
Calcitonin Gene

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.

Baseline tear fluid CGRP is elevated in active cluster headache patients as long as they have not taken attack abortive medication

Cephalalgia ◽  
2020 ◽  
pp. 033310242094985
Author(s):  
Katharina Kamm ◽  
Andreas Straube ◽  
Ruth Ruscheweyh
Keyword(s):  
Cluster Headache ◽  
Trigeminal Nerve ◽  
Calcitonin Gene Related Peptide ◽  
Chronic Cluster Headache ◽  
Tear Fluid ◽  
Abortive Medication ◽  
Related Peptide ◽  
Calcitonin Gene ◽  
Active Cluster ◽  
Headache Patients

Background Calcitonin gene-related peptide plays a key role in cluster headache pathophysiology. It is released from the trigeminal nerve, which also innervates the eye. In this study, we tested if tear fluid calcitonin gene-related peptide measurement detects elevated calcitonin gene-related peptide levels in cluster headache patients compared to controls. Methods Calcitonin gene-related peptide concentration in tear fluid and plasma of 16 active episodic and 11 chronic cluster headache patients (all outside acute attacks) and 60 controls were assessed using ELISA. Results Cluster headache patients without use of attack abortive medication in the last 48 h showed significantly elevated tear fluid calcitonin gene-related peptide levels (1.78 ± 1.57 ng/ml, n = 17) compared to healthy controls (0.79 ± 0.74 ng/ml, p = 0.003) and compared to cluster headache patients who had used attack abortive medication in the last 48 h (0.84 ± 1.40 ng/ml, n = 10, p = 0.022). High calcitonin gene-related peptide levels in cluster headache patients were independent of the occurrence of a cluster headache attack in the last 48 hours (no attack: 1.95 ± 1.65 ng/ml, n = 8; attack: 1.63 ± 1.59 ng/ml, n = 9, p = 0.82) as long as no acute medication was used. No significant difference in tear fluid calcitonin gene-related peptide levels between episodic (1.48 ± 1.34 ng/ml) and chronic cluster headache patients (2.21 ± 1.88 ng/ml, p = 0.364) was detected. In contrast to these results in tear fluid, there were no significant group differences in plasma calcitonin gene-related peptide levels. Conclusion This study shows that active cluster headache patients have increased calcitonin gene-related peptide levels in tear fluid compared to healthy subjects, which are reduced to control levels after intake of attack abortive medication. Calcitonin gene-related peptide measurement in tear fluid is non-invasive, and has the advantage of allowing direct access to calcitonin gene-related peptide released from the trigeminal nerve.

PACAP38- and VIP-induced cluster headache attacks are not associated with changes of plasma CGRP or markers of mast cell activation

Cephalalgia ◽  
2021 ◽  
pp. 033310242110562
Author(s):  
Lanfranco Pellesi ◽  
Basit Ali Chaudhry ◽  
Anne Luise Haulund Vollesen ◽  
Agneta Henriette Snoer ◽  
Katrine Baumann ◽  
...  
Keyword(s):  
Mast Cell ◽  
Cluster Headache ◽  
Vasoactive Intestinal Polypeptide ◽  
Plasma Levels ◽  
Cell Activation ◽  
Calcitonin Gene Related Peptide ◽  
Mast Cell Activation ◽  
Related Peptide ◽  
Calcitonin Gene ◽  
Headache Patients

Background Pituitary adenylate cyclase-activating polypeptide-38 (PACAP38) and vasoactive intestinal polypeptide can provoke cluster headache attacks in up to half of cluster headache patients in their active phase. At present, it is unknown whether provoked attacks are mediated via calcitonin gene-related peptide or mast cell activation. Methods All enrolled patients with cluster headache were randomly allocated to receive a continuous infusion of either PACAP38 (10 pmol/kg/min) or vasoactive intestinal polypeptide (8 pmol/kg/min) over 20 min. We collected clinical data and measured plasma levels of calcitonin gene-related peptide and markers of mast cell activation (tryptase and histamine) at fixed time points: at baseline (T0), at the end of the infusion (T20), 10 min after the infusion (T30), and 70 min after the infusion (T90). Results Blood was collected from episodic cluster headache patients in active phase (n = 14), episodic cluster headache patients in remission (n = 15), and chronic cluster headache patients (n = 15). At baseline, plasma levels of calcitonin gene-related peptide, tryptase, and histamine were not different among the three study groups. Plasma levels of calcitonin gene-related peptide ( p = 0.7074), tryptase ( p = 0.6673), or histamine ( p = 0.4792) remained unchanged during provoked attacks compared to attack-free patients. Conclusion Cluster headache attacks provoked by either PACAP38 or vasoactive intestinal polypeptide were not accompanied by alterations of plasma calcitonin gene-related peptide, tryptase or histamine. The provoked attacks may not be mediated by calcitonin gene-related peptide or mast cell activation. Trial Registration: The study is registered at ClinicalTrials.gov (NCT03814226).

scholarly journals Calcitonin gene-related peptide and disease activity in cluster headache

Cephalalgia ◽  
2019 ◽  
Vol 39 (5) ◽  
pp. 575-584 ◽  
Author(s):  
Agneta Snoer ◽  
Anne Luise H Vollesen ◽  
Rasmus P Beske ◽  
Song Guo ◽  
Jan Hoffmann ◽  
...  
Keyword(s):  
Cluster Headache ◽  
Vasoactive Intestinal Polypeptide ◽  
Active Phase ◽  
Calcitonin Gene Related Peptide ◽  
Chronic Cluster Headache ◽  
Related Peptide ◽  
Episodic Cluster Headache ◽  
Calcitonin Gene ◽  
Headache Patients ◽  
Intestinal Polypeptide

Objective To investigate the role of calcitonin gene-related peptide, pituitary adenylate cyclase-activating polypeptide-38 (PACAP38) and vasoactive intestinal polypeptide in cluster headache, we measured these vasoactive peptides interictally and during experimentally induced cluster headache attacks. Methods We included patients with episodic cluster headache in an active phase (n = 9), episodic cluster headache patients in remission (n = 9) and patients with chronic cluster headache (n = 13). Cluster headache attacks were induced by infusion of calcitonin gene-related peptide (1.5 µg/min) in a randomized, double-blind, placebo controlled, two-way cross-over study. At baseline, we collected interictal blood samples from all patients and during 11 calcitonin gene-related peptide-induced cluster headache attacks. Results At baseline, episodic cluster headache patients in remission had higher plasma levels of calcitonin gene-related peptide, 100.6 ± 36.3 pmol/l, compared to chronic cluster headache patients, 65.9 ± 30.5 pmol/l, ( p = 0.011). Episodic cluster headache patients in active phase had higher PACAP38 levels, 4.0 ± 0.8 pmol/l, compared to chronic cluster headache patients, 3.3 ± 0.7 pmol/l, ( p = 0.033). Baseline levels of vasoactive intestinal polypeptide did not differ between cluster headache groups. We found no attack-related increase in calcitonin gene-related peptide, PACAP38 or vasoactive intestinal polypeptide levels during calcitonin gene-related peptide-induced cluster headache attacks. Conclusions This study suggests that cluster headache disease activity is associated with alterations of calcitonin gene-related peptide expression. Future studies should investigate the potential of using calcitonin gene-related peptide measurements in monitoring of disease state and predicting response to preventive treatments, including response to anti-calcitonin gene-related peptide monoclonal antibodies.

Calcitonin gene-related peptide receptors in rat trigeminal ganglion do not control spinal trigeminal activity

2012 ◽  
Vol 108 (2) ◽  
pp. 431-440 ◽  
Author(s):  
Oana Covasala ◽  
Sören L. Stirn ◽  
Stephanie Albrecht ◽  
Roberto De Col ◽  
Karl Messlinger
Keyword(s):  
Trigeminal Ganglion ◽  
Dura Mater ◽  
Calcitonin Gene Related Peptide ◽  
Afferent Input ◽  
Nitric Oxide Donor ◽  
Cgrp Receptor ◽  
Related Peptide ◽  
Trigeminal Neurons ◽  
Calcitonin Gene ◽  
Evoked Activity

Calcitonin gene-related peptide (CGRP) is regarded as a key mediator in the generation of primary headaches. CGRP receptor antagonists reduce migraine pain in clinical trials and spinal trigeminal activity in animal experiments. The site of CGRP receptor inhibition causing these effects is debated. Activation and inhibition of CGRP receptors in the trigeminal ganglion may influence the activity of trigeminal afferents and hence of spinal trigeminal neurons. In anesthetized rats extracellular activity was recorded from neurons with meningeal afferent input in the spinal trigeminal nucleus caudalis. Mechanical stimuli were applied at regular intervals to receptive fields located in the exposed cranial dura mater. α-CGRP (10−5 M), the CGRP receptor antagonist olcegepant (10−3 M), or vehicle was injected through the infraorbital canal into the trigeminal ganglion. The injection of volumes caused transient discharges, but vehicle, CGRP, or olcegepant injection was not followed by significant changes in ongoing or mechanically evoked activity. In animals pretreated intravenously with the nitric oxide donor glyceryl trinitrate (GTN, 250 μg/kg) the mechanically evoked activity decreased after injection of CGRP and increased after injection of olcegepant. In conclusion, the activity of spinal trigeminal neurons with meningeal afferent input is normally not controlled by CGRP receptor activation or inhibition in the trigeminal ganglion. CGRP receptors in the trigeminal ganglion may influence neuronal activity evoked by mechanical stimulation of meningeal afferents only after pretreatment with GTN. Since it has previously been shown that olcegepant applied to the cranial dura mater is ineffective, trigeminal activity driven by meningeal afferent input is more likely to be controlled by CGRP receptors located centrally to the trigeminal ganglion.

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