Vasoactive peptide release in the extracerebral circulation of humans during migraine headache

Goadsby, Peter J.; Edvinsson, Lars; Ekman, Rolf

doi:10.1002/ana.410280213

Cited by 1,380 publications

(1,062 citation statements)

References 27 publications

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“…A Ca 2+ -dependent and capsaicin-sensitive release of CGRP, but not SP, has been documented from human tissues containing non-trigeminal [13] or trigeminal [11] sensory nerve endings. Furthermore, plasma concentrations of CGRP, but not of SP, were elevated during the headache phase of migraine [64] and cluster headache [65]. There is evidence that intravenous infusion of CGRP produces a migraine-like headache [66], and intravenous infusion of nitric oxide produces a migraine-like headache with an associated increase in plasma CGRP levels [67].…”

Section: Migraine and Neurogenic Inflammationmentioning

confidence: 99%

CGRP and migraine: neurogenic inflammation revisited

Geppetti

Capone²,

Trevisani

et al. 2005

J Headache Pain

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The term 'neurogenic inflammation' refers to a series of proinflammatory responses produced by the stimulation of peripheral terminals of a subset of primary sensory neurons and the subsequent release of the neuropeptides, calcitonin gene-related peptide (CGRP) and the tachykinins, substance P (SP) and neurokinin A (NKA) [1]. The neurons that produce inflammation comprise a heterogeneous cell population with A-delta and C fibres, defined as polymodal nociceptors because they sense thermal, chemical and high-threshold mechanical stimuli. These neurons express on their plasma membrane a large panel of excitatory and inhibitory receptors and channels, and some of these signalling proteins have been successfully used as targets for analgesic or anti-inflammatory drugs. Among the channels expressed on peptidergic primary sensory neurons, transient receptor potential vanilloid-1 (TRPV1) [2], activated by the xenobiotic capsaicin, the pungent ingredient of plants of the genus Capsicum, is of paramount importance. Capsaicin produces burning pain by stimulating TRPV1 and by releasing sensory neuropeptides causes neurogenic inflammation. However, high concentrations/doses of capsaicin have the ability, after an initial excitatory phase, to desensitise the sensory nerve terminals, thus reducing the transmission of sensory/pain signals and abolishing neurogenic inflammation [3, 4]. This specific feature of capsaicin has greatly contributed to define the role of this subset of sensory nerves in pathophysiological models of human diseases and has been Pierangelo Geppetti Jay Guido Capone Marcello Trevisani Paola Nicoletti Giovanni Zagli Maria Rosalia Tola Abstract For more than a century neurogenic inflammation has been proposed to have a role in various human diseases. The present review will cover the conceptual steps of the itinerary that has led to the conclusion that neurogenic inflammation is important in migraine. Of particular relevance for the object of this article is the observation that tachykinindependent neurogenic inflammatory responses are evident in rodents, but much less pronounced or absent in other mammal species, including man, whereas neurogenic vasodilatation, most likely mediated by CGRP, occurs in most mammalian species and also in man. Recent evidence that a CGRP receptor antagonist was effective in the treatment of migraine attack supports the hypothesis that neurogenic vasodilatation is a major underlying mechanism of migraine.

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Section: Migraine and Neurogenic Inflammationmentioning

confidence: 99%

CGRP and migraine: neurogenic inflammation revisited

Geppetti

Capone²,

Trevisani

et al. 2005

J Headache Pain

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“…Upon stimulation, CGRP can be released from these nerve fibres both in vitro and in vivo and cause vasodilatation. For instance, this occurs both in cardiovascular system following ischaemia (Kallner, 1998), during migraine headache (Goadsby et al, 1990) and following subarachnoid haemorrhage (Juul et al, 1990).…”

Section: Introductionmentioning

confidence: 99%

Noncompetitive antagonism of BIBN4096BS on CGRP‐induced responses in human subcutaneous arteries

Sheykhzade

Lind

Edvinsson

2004

British J Pharmacology

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1 We investigated the antagonistic effect of 1-piperidinecarboxamide, N-[2-[[5amino-l-[[4-(4-pyridinyl)-l-piperazinyl]carbonyl]pentyl]amino]-1- [(3,5-dibromo-4-hydroxyphenyl)methyl]-2-oxoethyl]-4-(1,4-dihydro-2-oxo-3(2H)-quinazolinyl) (BIBN4096BS) on the calcitonin gene-related peptide (CGRP)-induced responses by using isometric myograph and FURA-2 technique in human subcutaneous arteries removed in association with abdominal surgery. 2 BIBN4096BS, at the concentration of 1 pM, had no significant effect on the CGRP-induced relaxation in these vessels. 3 At the concentration of 10 pM, BIBN4096BS had a competitive antagonistic-like behaviour characterized by parallel rightward shift in the log CGRP concentration-tension curve with no depression of the E max . 4 At the higher concentrations (0.1 and 1 nM), BIBN4096BS had a concentration-dependent noncompetitive antagonistic effect on the CGRP-induced responses. 5 The efficacy and potency of CGRP was significantly greater in the smaller (lumen diameter B200 mm) human subcutaneous arteries compared to the larger ones. 6 The apparent agonist equilibrium dissociation constant, K A , for CGRP 1 receptors in the human subcutaneous arteries was approximately 1 nM. Analysis of the relationship between receptor occupancy and response to CGRP indicates that the receptor reserve is relatively small. 7 Using reverse transcriptase-polymerase chain reaction (RT-PCR), the presence of mRNA sequences encoding the calcitonin receptor-like receptor, receptor activity modifying protein (RAMP1, RAMP2, RAMP3) and receptor component protein were demonstrated in human subcutaneous arteries, indicating the presence of CGRP 1 -like receptor and the necessary component for the receptor activation. 8 In conclusion, the inhibitory action of BIBN4096BS at the low concentration (10 pM) on the CGRP-tension curve (but not intracellular calcium concentration ([Ca 2 þ ] i ) resembles what is seen with a reversible competitive antagonist. However, at the higher concentrations (0.1 and 1 nM), BIBN4096BS acts as a selective noncompetitive inhibitor at CGRP 1 receptors in human subcutaneous arteries.

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“…Elevated levels of CGRP, but not of other neuropeptides, were found in the external jugular vein during the headache phase of migraine and normalized in parallel with headache improvement [22,23]. Furthermore, infusion of human CGRP was found to trigger a migraine attack in susceptible individuals, while normalization of CGRP levels were obtained after migraine treatment with triptans [24][25][26].…”

Section: Pathophysiologymentioning

confidence: 97%

Targeting CGRP: A New Era for Migraine Treatment

Goldberg

Silberstein

2015

CNS Drugs

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Migraine is a highly prevalent headache disease that typically affects patients during their most productive years. Despite significant progress in understanding the underlying pathophysiology of this disorder, its treatment so far continues to depend on drugs that, in their majority, were not specifically designed for this purpose. The neuropeptide calcitonin gene-related peptide (CGRP) has been indicated as playing a critical role in the central and peripheral pathways leading to a migraine attack. It is not surprising that drugs designed to specifically block its action are gaining remarkable attention from researchers in the field with, at least so far, a safe risk profile. In this article, we highlight the evolution from older traditional treatments to the innovative CGRP target drugs that are revolutionizing the way to approach this debilitating neurological disease. We provide a brief introduction on pathophysiology of migraine and details on the characteristic, function, and localization of CGRP to then focus on CGRP receptor antagonists (CGRP-RAs) and CGRP monoclonal antibodies (CGRP mAbs). Key PointsThe neuropeptide calcitonin gene-related peptide (CGRP) has been indicated as playing a critical role in the central and peripheral pathways leading to a migraine attack.Targeting CGRP as a specific therapeutic tool for migraine may offer similar or even better efficacy than currently available treatments without the vasoconstrictive risk factors.Further studies are necessary to determine the exact role of CGRP receptor antagonists and CGRP monoclonal antibodies in migraine with aura, allodynia, and photophobia.

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Vasoactive peptide release in the extracerebral circulation of humans during migraine headache

Cited by 1,380 publications

References 27 publications

CGRP and migraine: neurogenic inflammation revisited

CGRP and migraine: neurogenic inflammation revisited

Noncompetitive antagonism of BIBN4096BS on CGRP‐induced responses in human subcutaneous arteries

Targeting CGRP: A New Era for Migraine Treatment

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