Neuropeptides in Migraine and Cluster Headache

Edvinsson, Lars; Goadsby, PJ

doi:10.1046/j.1468-2982.1994.1405320.x

Cited by 171 publications

(100 citation statements)

References 51 publications

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“…We also investigated whether sumatriptan could inhibit the release of the vasoactive neuropeptide substance P, because it has been reported to colocalize with CGRP in sensory neurons (Edvinsson and Goadsby, 1994) and is involved in mediating neurogenic inflammation (Buzzi et al, 1995). In preliminary studies, we determined that sumatriptan could also inhibit the KClstimulated release of substance P (data not shown).…”

Section: Sumatriptan Represses Stimulated Cgrp Releasementioning

confidence: 99%

Regulation of Calcitonin Gene-Related Peptide Secretion by a Serotonergic Antimigraine Drug

1999

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We have investigated the regulation of calcitonin gene-related peptide (CGRP) release from trigeminal neurons by the serotonergic antimigraine drug sumatriptan. Serum levels of the neuropeptide CGRP are elevated during migraine. Treatment with the drug sumatriptan returns CGRP levels to normal coincident with the alleviation of headache. However, despite this clinical efficacy, the cellular target and mechanism of sumatriptan action are not well understood beyond the pharmacology of its recognition of the 5-HT 1 class of serotonin receptors. We have used cultured trigeminal neurons to demonstrate that sumatriptan can directly repress CGRP secretion from sensory neurons. The stimulated secretion in response to depolarization or inflammatory agents was inhibited, but not the basal secretion rate. Unexpectedly, sumatriptan did not lower cAMP levels, in contrast to the classical role ascribed to the 5-HT 1 receptors. Instead, activation of 5-HT 1 receptors caused a slow and remarkably prolonged increase in intracellular calcium. The inhibition of CGRP secretion is attenuated by the phosphatase inhibitor okadaic acid, suggesting that sumatriptan action is mediated by calcium-recruited phosphatases. These results suggest that 5-HT 1 agonists may block a deleterious feedback loop in migraine at the trigeminal neurons and provide a general mechanism by which this class of drugs can attenuate stimulated neuropeptide release. Key words: CGRP; serotonin receptors; trigeminal neurons; calcium; phosphatase; migraine; neuropeptideCalcitonin gene-related peptide (CGRP) is a 37 amino acid regulatory neuropeptide derived from alternative splicing of the calcitonin /CGRP gene (Rosenfeld et al., 1983). During migraine, a painf ul neurological disorder afflicting 16% of the general population (Stewart et al., 1994), activation of trigeminal neurons leads to increased secretion of CGRP (Moskowitz, 1993). Together with substance P and neurokinin A, CGRP helps mediate neurogenic inflammation, a condition characterized by vasodilation, plasma protein extravasation, and mast cell degranulation (Buzzi et al., 1995). CGRP is the most potent vasodilatory neuropeptide known (McCulloch et al., 1986) and recently has been shown to cause dural mast cell degranulation (Ottosson and Edvinsson, 1997). CGRP is also believed to convey nociceptive information from the vasculature to the C NS (Van Rossum et al., 1997). On the basis of these data, CGRP is believed to play a key role in the painf ul phase of migraine. This belief has been strongly supported by the clinical efficacy of the selective 5-HT 1 receptor drug sumatriptan (Ferrari, 1998). Sumatriptan has been shown to decrease the elevated CGRP levels in migraine patients, coincident with relief of headache pain (Goadsby and Edvinsson, 1993). Trigeminal nerves play an important role in the regulation of cerebral blood flow during normal and disease states and are the major source of sensory and CGRP innervation to the cerebral vasculature (McCulloch et al., 1986;O'Conner and Van Der Kooy, 1988...

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Section: Sumatriptan Represses Stimulated Cgrp Releasementioning

confidence: 99%

Regulation of Calcitonin Gene-Related Peptide Secretion by a Serotonergic Antimigraine Drug

1999

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“…CGRP is known to promote inflammation and nociception (van Rossum et al, 1997). Elevated levels of CGRP have been reported to correlate with pain severity during migraine attacks (Buzzi and Moskowitz, 1992;Edvinsson and Goadsby, 1994) and TMJD (Holmlund et al, 1991;Appelgren et al, 1993). TMJD is a clinical term used to describe the number of related disorders affecting the jaw joint, masticatory muscle and associated structures (Schiffman et al, 1990).…”

Section: Introductionmentioning

confidence: 99%

Repression of calcitonin gene-related peptide expression in trigeminal neurons by a Theobroma cacao extract

Abbey

Patil

Vause

et al. 2008

Journal of Ethnopharmacology

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Ethnopharmacological relevance-Cocoa bean preparations were first used by the ancient Maya and Aztec civilizations of South America to treat a variety of medical ailments involving the cardiovascular, gastrointestinal, and nervous systems. Diets rich in foods containing abundant polyphenols, as found in cocoa, underlie the protective effects reported in chronic inflammatory diseases. Release of calcitonin gene-related peptide (CGRP) from trigeminal nerves promotes inflammation in peripheral tissues and nociception.Aim of the study-To determine whether a methanol extract of Theobroma cacao L. (Sterculiaceae) beans enriched for polyphenols could inhibit CGRP expression, both an in vitro and an in vivo approach was taken.Results-Treatment of rat trigeminal ganglia cultures with depolarizing stimuli caused a significant increase in CGRP release that was repressed by pretreatment with Theobroma cacao extract. Pretreatment with Theobroma cacao was also shown to block the KCl-and capsaicin-stimulated increases in intracellular calcium. Next, the effects of Theobroma cacao on CGRP levels were determined using an in vivo model of temporomandibular joint (TMJ) inflammation. Capsaicin injection into the TMJ capsule caused an ipsilateral decrease in CGRP levels. Theobroma cacao extract injected into the TMJ capsule 24 h prior to capsaicin treatment repressed the stimulatory effects of capsaicin.Conclusions-Our results demonstrate that Theobroma cacao extract can repress stimulated CGRP release by a mechanism that likely involves blockage of calcium channel activity. Furthermore, our findings suggest that the beneficial effects of diets rich in cocoa may include suppression of sensory trigeminal nerve activation.

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“…CGRP has pleiotrophic effects but has been best characterized as a potent vasodilatory neuropeptide (4,5). Elevated CGRP levels have been detected in some cardiovascular disorders (5) and in vascular headaches (6). The CT/CGRP gene is transcribed in a large number of neurons of the peripheral and central nervous systems and in the neuroendocrine thyroid C cells.…”

mentioning

confidence: 99%

Binding of Upstream Stimulatory Factor and a Cell-specific Activator to the Calcitonin/Calcitonin Gene-related Peptide Enhancer

Lanigan

Russo

1997

Journal of Biological Chemistry

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The calcitonin/calcitonin gene-related peptide (CT/ CGRP) gene is selectively transcribed in thyroid C cells and neurons. We have previously shown that the rat CT/CGRP cell-specific enhancer is synergistically regulated by a helix-loop-helix (HLH) protein and the OB2 octamer-binding protein. In this report, we show that the HLH-OB2 enhancer is required for full promoter activity, even in the context of other HLH elements.Since this enhancer appears to be a major controlling element, we have characterized the HLH and OB2 DNA binding proteins. We have identified the major HLH complex as a heterodimer of the ubiquitous upstream stimulatory factor (USF)-1 and USF-2 proteins. USF bound the enhancer with a reasonably high affinity (K D 1.6 nM), comparable to other genes. Characterization of a series of mutations revealed that a portion of the HLH motif is also recognized by OB2 and confirmed that HLH activity requires OB2. We have shown that OB2 is a single DNA binding protein based on UV cross-linking studies. The 68-kDa protein-DNA complex was detected only in C cell lines, including a human C cell line that has robust HLH-OB2 enhancer activity. These results suggest that the calcitonin/CGRP gene is controlled by the combinatorial activity of a ubiquitous USF HLH heterodimer and an associated cell-specific activator.

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Neuropeptides in Migraine and Cluster Headache

Cited by 171 publications

References 51 publications

Regulation of Calcitonin Gene-Related Peptide Secretion by a Serotonergic Antimigraine Drug

Regulation of Calcitonin Gene-Related Peptide Secretion by a Serotonergic Antimigraine Drug

Repression of calcitonin gene-related peptide expression in trigeminal neurons by a Theobroma cacao extract

Binding of Upstream Stimulatory Factor and a Cell-specific Activator to the Calcitonin/Calcitonin Gene-related Peptide Enhancer

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