Differentiation of Nerve Fibers Storing CGRP and CGRP Receptors in the Peripheral Trigeminovascular System

Eftekhari, Sajedeh; Warfvinge, Karin; Blixt, Frank W; Edvinsson, Lars

doi:10.1016/j.jpain.2013.03.010

Cited by 210 publications

(164 citation statements)

References 53 publications

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“…This distribution is consistent with the role of CGRP as a primary afferent transmitter. 64,68,69,119 Calcitonin gene-related peptide is also found in peripheral fibers innervating the heart, coronary arteries, vascular beds, and myenteric system. 157,159,160,190 The CGRP receptor is highly concentrated in the spinal cord, particularly the dorsal horns of the spinal cord and cerebral gray matter, and overlaps with the distribution of CGRP protein.…”

Section: Calcitonin Gene–related Peptide and The Calcitonin Gene–rmentioning

confidence: 99%

“…High densities of binding for [ 125 I]CGRP were found in the molecular layer and Purkinje cell layer of the human cerebellum 69 and for [ 3 H]MK-3207 in the molecular layer of rhesus cerebellum, 67 suggesting the possibility of a functional role in primate cerebellar cortex. Using the radiolabeled compound [ 11 C]MK-4232 as a tracer for identification of CGRP-binding sites, positron emission tomography (PET) found the highest concentrations of CGRP receptors in the cerebellum and brainstem of rhesus monkeys and the cerebellum of humans.…”

Section: Calcitonin Gene–related Peptide and The Calcitonin Gene–rmentioning

confidence: 99%

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The role of calcitonin gene–related peptide in peripheral and central pain mechanisms including migraine

Iyengar

Ossipov²,

Johnson

2017

Pain

446

364

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Calcitonin gene–related peptide (CGRP) is a 37-amino acid peptide found primarily in the C and Aδ sensory fibers arising from the dorsal root and trigeminal ganglia, as well as the central nervous system. Calcitonin gene–related peptide was found to play important roles in cardiovascular, digestive, and sensory functions. Although the vasodilatory properties of CGRP are well documented, its somatosensory function regarding modulation of neuronal sensitization and of enhanced pain has received considerable attention recently. Growing evidence indicates that CGRP plays a key role in the development of peripheral sensitization and the associated enhanced pain. Calcitonin gene–related peptide is implicated in the development of neurogenic inflammation and it is upregulated in conditions of inflammatory and neuropathic pain. It is most likely that CGRP facilitates nociceptive transmission and contributes to the development and maintenance of a sensitized, hyperresponsive state not only of the primary afferent sensory neurons but also of the second-order pain transmission neurons within the central nervous system, thus contributing to central sensitization as well. The maintenance of a sensitized neuronal condition is believed to be an important factor underlying migraine. Recent successful clinical studies have shown that blocking the function of CGRP can alleviate migraine. However, the mechanisms through which CGRP may contribute to migraine are still not fully understood. We reviewed the role of CGRP in primary afferents, the dorsal root ganglion, and in the trigeminal system as well as its role in peripheral and central sensitization and its potential contribution to pain processing and to migraine.

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Section: Calcitonin Gene–related Peptide and The Calcitonin Gene–rmentioning

confidence: 99%

Section: Calcitonin Gene–related Peptide and The Calcitonin Gene–rmentioning

confidence: 99%

The role of calcitonin gene–related peptide in peripheral and central pain mechanisms including migraine

Iyengar

Ossipov²,

Johnson

2017

Pain

446

364

View full text Add to dashboard Cite

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“…Receptor-wise, activation/upregulation of meningeal nociceptors by each of the above-mentioned scenarios may involve one or more of the many receptors found in the dura. These include receptors such as the transient receptor potential (TRP) channels TRPV1, TRPA1 and TRPM8 (20), ATP-gated P2X3 receptors (21), dopaminergic D1 and D2 receptors (22), serotonergic 5HT1b/1d receptors (23,24), the calcitonin gene-related peptide (CGRP) receptor calcitonin receptor-like receptor/receptor activity-modifying protein-1 (CRLR/RAMP1) (25), tumor necrosis factor (TNF)-α (26), and acid-sensing ion channel 3 (ASIC3) (15). Collectively, these receptors can promote mechanical and chemical activation and/or sensitization of meningeal nociceptors.…”

Section: Introductionmentioning

confidence: 99%

Selective inhibition of meningeal nociceptors by botulinum neurotoxin type A: Therapeutic implications for migraine and other pains

et al. 2014

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Background Meningeal and other trigeminal nociceptors are thought to play important roles in the initiation of migraine headache. Currently, the only approved peripherally administered chronic migraine prophylactic drug is onabotulinumtoxinA. The purpose of this study was to determine how botulinum neurotoxin type A (BoNT-A) affects naïve and sensitized meningeal nociceptors. Material and methods Using electrophysiological techniques, we identified 43 C- and 36 Aδ-meningeal nociceptors, and measured their spontaneous and evoked firing before and after BoNT-A administration to intracranial dura and extracranial suture-receptive fields. Results As a rule, BoNT-A inhibited C- but not Aδ-meningeal nociceptors. When applied to nonsensitized C-units, BoNT-A inhibited responses to mechanical stimulation of the dura with suprathreshold forces. When applied to sensitized units, BoNT-A reversed mechanical hypersensitivity. When applied before sensitization, BoNT-A prevented development of mechanical hypersensitivity. When applied extracranially to suture branches of intracranial meningeal nociceptors, BoNT-A inhibited the mechanical responsiveness of the suture branch but not dural axon. In contrast, BoNT-A did not inhibit C-unit responses to mechanical stimulation of the dura with threshold forces, or their spontaneous activity. Discussion The study provides evidence for the ability of BoNT-A to inhibit mechanical nociception in peripheral trigeminovascular neurons. These findings suggest that BoNT-A interferes with neuronal surface expression of high-threshold mechanosensitive ion channels linked preferentially to mechanical pain by preventing their fusion into the nerve terminal membrane.

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“…The ophthalmic branch senses information from the blood vessels which irrigate meninges [182]. Furthermore, blood vessels from dura mater are rich in expressing CGRP receptors, specifically on the smooth muscle cells [183]. Hence, expression of CGRP receptors at the peripheral level seems to be mainly postjunctional.…”

Section: The Role Of Cgrp On Some Vascular-related Diseasesmentioning

confidence: 99%

Heteroreceptors Modulating CGRP Release at Neurovascular Junction: Potential Therapeutic Implications on Some Vascular-Related Diseases

González‐Hernández

Marichal‐Cancino

Lozano-Cuenca

et al. 2016

BioMed Research International

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Calcitonin gene-related peptide (CGRP) is a 37-amino-acid neuropeptide belonging to the calcitonin gene peptide superfamily. CGRP is a potent vasodilator with potential therapeutic usefulness for treating vascular-related disease. This peptide is primarily located on C- and Aδ-fibers, which have extensive perivascular presence and a dual sensory-efferent function. Although CGRP has two major isoforms (α-CGRP and β-CGRP), the α-CGRP is the isoform related to vascular actions. Release of CGRP from afferent perivascular nerve terminals has been shown to result in vasodilatation, an effect mediated by at least one receptor (the CGRP receptor). This receptor is an atypical G-protein coupled receptor (GPCR) composed of three functional proteins: (i) the calcitonin receptor-like receptor (CRLR; a seven-transmembrane protein), (ii) the activity-modifying protein type 1 (RAMP1), and (iii) a receptor component protein (RCP). Although under physiological conditions, CGRP seems not to play an important role in vascular tone regulation, this peptide has been strongly related as a key player in migraine and other vascular-related disorders (e.g., hypertension and preeclampsia). The present review aims at providing an overview on the role of sensory fibers and CGRP release on the modulation of vascular tone.

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Differentiation of Nerve Fibers Storing CGRP and CGRP Receptors in the Peripheral Trigeminovascular System

Cited by 210 publications

References 53 publications

The role of calcitonin gene–related peptide in peripheral and central pain mechanisms including migraine

The role of calcitonin gene–related peptide in peripheral and central pain mechanisms including migraine

Selective inhibition of meningeal nociceptors by botulinum neurotoxin type A: Therapeutic implications for migraine and other pains

Heteroreceptors Modulating CGRP Release at Neurovascular Junction: Potential Therapeutic Implications on Some Vascular-Related Diseases

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