Calcitonin receptor‐like receptor (CLR), receptor activity‐modifying protein 1 (RAMP1), and calcitonin gene‐related peptide (CGRP) immunoreactivity in the rat trigeminovascular system: Differences between peripheral and central CGRP receptor distribution

Lennerz, Jochen K.; Rühle, Victor; Ceppa, Eugene P.; Neuhuber, Winfried; Bunnett, Nigel W.; Grady, Eileen F.; Meßlinger, Karl

doi:10.1002/cne.21654

Cited by 48 publications

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“…We observed that neurons positive for CGRP were mostly negative for the receptor components CLR and RAMP1. Almost 50% of human trigeminal neurons expressed CGRP, which is in agreement with previous studies in man (Tajti et al, 1999) and rat (Ma et al, 2001, Lennerz et al, 2008. Expression of CLR and RAMP1 was seen in approximately 40% of the neurons.…”

Section: The Distribution Of Cgrp and The Receptor Componentssupporting

confidence: 91%

“…Expression of CLR and RAMP1 was seen in approximately 40% of the neurons. In a study on rat trigeminal ganglion, it was reported that CLR was more frequently expressed than RAMP1 in the neurons (Lennerz et al, 2008). The dissimilarity between these results and ours could be due to several factors such as the use of different primary antibodies, cell-counting method or differences between human and rat trigeminal ganglia.…”

Section: The Distribution Of Cgrp and The Receptor Componentscontrasting

confidence: 80%

“…The localization of the CGRP receptor elements in the trigeminovascular system has not been fully clarified to date (Lennerz et al, 2008). We have previously reported the expression of CLR and RAMP1 on smooth muscle cells in human cerebral and meningeal arteries and of CGRP receptor mRNA in human cerebral vessels and trigeminal ganglion (Edvinsson et al, 1997).…”

Section: The Distribution Of Cgrp and The Receptor Componentsmentioning

confidence: 99%

“…Studies performed on rat trigeminal ganglion also demonstrated the expression of the CGRP receptor components on satellite glial cells (Lennerz et al, 2008, Li et al, 2008. The function of this localization needs to evaluated, however expression of receptors in satellite glial cells suggest that they can receive signals from CGRP positive neurons and potentially respond to activate local inflammatory signals.…”

Section: The Glial Cellsmentioning

confidence: 99%

“…Earlier it was believed that the main function of glial cells was that of neuronal support; however during the last decade it has been revealed that the satellite glial cells may modulate neuronal function and activity, and could therefore be a factor in migraine pathophysiology (Hanani, 2005, Dublin and Hanani, 2007, Thalakoti et al, 2007, Li et al, 2008 Immunohistochemical studies performed on the trigeminal system have shown CGRP immunoreactivity in about 50 % of the neurons of human and rat trigeminal ganglion (Tajti et al, 1999, Lennerz et al, 2008. The elegant work of Lennerz and co-workers also demonstrated CLR and RAMP1 within the rat trigeminal ganglion.…”

Section: Introductionmentioning

confidence: 99%

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Differential distribution of calcitonin gene-related peptide and its receptor components in the human trigeminal ganglion

et al. 2010

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"Differential distribution of calcitonin gene-related peptide (CGRP) and CGRP receptor components (CLR and RAMP1) in the human trigeminal ganglion."Neuroscience, 2010, Jun 2 http://dx.doi.org/10.1016/j.neuroscience.2010.05.016Access to the published version may require journal subscription.Published with permission from: Elsevier Antibodies against purified CLR and RAMP1 proteins were produced and characterized for this study. Trigeminal ganglia were obtained at autopsy from adult subjects and sections from rat trigeminal ganglia were used to compare the immunostaining pattern. The number of cells expressing CGRP, CLR and RAMP1, respectively, were counted. In addition, the glial cells of trigeminal ganglion, particularly the satellite glial cell, were studied to understand a possible relation.We observed immunoreactivity for CGRP, CLR and RAMP1, in the human trigeminal ganglion: 49% of the neurons expressed CGRP, 37% CLR and 36% RAMP1. Co-localization of CGRP and the receptor components was rarely found. There were no CGRP immunoreactions in the glial cells; however some of the glial cells displayed CLR and RAMP1 immunoreactivity. Similar results were observed in rat trigeminal ganglia.We report that human and rat trigeminal neurons store CGRP, CLR and RAMP1, however, CGRP and CLR/RAMP1 do not co-localize regularly but are found in separate neurons. Glial cells also contain the CGRP receptor components but not CGRP. Our results indicate, for the first time, the possibility of CGRP signaling in the human trigeminal ganglion involving both neurons and satellite glial cells. This suggests a possible site of action for the novel CGRP receptor antagonists in migraine therapy.

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Section: The Distribution Of Cgrp and The Receptor Componentssupporting

confidence: 91%

Section: The Distribution Of Cgrp and The Receptor Componentscontrasting

confidence: 80%

Section: The Distribution Of Cgrp and The Receptor Componentsmentioning

confidence: 99%

Section: The Glial Cellsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Differential distribution of calcitonin gene-related peptide and its receptor components in the human trigeminal ganglion

et al. 2010

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Hypersensitivity to Calcitonin Gene–Related Peptide in Post‐Traumatic Headache

Ashina

Iljazi

Al-Khazali

et al. 2020

Annals of Neurology

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Objective: To demonstrate that calcitonin gene-related peptide (CGRP) induces headache exacerbation with migraine-like features in patients with persistent post-traumatic headache (PTH) attributed to mild traumatic brain injury (TBI). Methods: A randomized, double-blind, placebo-controlled, two-way crossover study was conducted. Analyses were intention-to-treat. Eligible patients were aged 18 to 65 years and had a history of persistent PTH after mild TBI for at least 12 months. Patients were randomized to receive an intravenous infusion of 1.5μg/min of CGRP or placebo (isotonic saline) over 20 minutes on two separate experimental days. A 12-hour observational period was used to evaluate the following outcomes: (1) difference in incidence of headache exacerbation with migraine-like features and (2) difference in area under the curve for headache intensity scores. Results: Thirty patients (mean age = 37 years, 25 women [83%]) were randomized and completed the study. During the 12-hour observational period, 21 of 30 patients (70%) developed headache exacerbation with migraine-like features after CGRP, compared with 6 patients (20%) after placebo (p < 0.001). The baseline-corrected area under the curve for headache intensity scores was significantly larger after CGRP, compared with placebo (p < 0.001). Interpretation: Patients with persistent PTH are hypersensitive to CGRP, which underscores its pathophysiological importance. Furthermore, CGRP-targeted therapies might provide a novel mechanism-based treatment option for patients with persistent PTH.

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Meningeal CGRP‐Prolactin Interaction Evokes Female‐Specific Migraine Behavior

Avona

Mason

Burgos-Vega

et al. 2021

Annals of Neurology

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Objective Migraine is three times more common in women. CGRP plays a critical role in migraine pathology and causes female‐specific behavioral responses upon meningeal application. These effects are likely mediated through interactions of CGRP with signaling systems specific to females. Prolactin (PRL) levels have been correlated with migraine attacks. Here, we explore a potential interaction between CGRP and PRL in the meninges. Methods Prolactin, CGRP, and receptor antagonists CGRP8‐37 or Δ1‐9‐G129R‐hPRL were administered onto the dura of rodents followed by behavioral testing. Immunohistochemistry was used to examine PRL, CGRP and Prolactin receptor (Prlr) expression within the dura. Electrophysiology on cultured and back‐labeled trigeminal ganglia (TG) neurons was used to assess PRL‐induced excitability. Finally, the effects of PRL on evoked CGRP release from ex vivo dura were measured. Results We found that dural PRL produced sustained and long‐lasting migraine‐like behavior in cycling and ovariectomized female, but not male rodents. Prlr was expressed on dural afferent nerves in females with little‐to‐no presence in males. Consistent with this, PRL increased excitability only in female TG neurons innervating the dura and selectively sensitized CGRP release from female ex vivo dura. We demonstrate crosstalk between PRL and CGRP systems as CGRP8‐37 decreases migraine‐like responses to dural PRL. Reciprocally, Δ1‐9‐G129R‐hPRL attenuates dural CGRP‐induced migraine behaviors. Similarly, Prlr deletion from sensory neurons significantly reduced migraine‐like responses to dural CGRP. Interpretation This CGRP‐PRL interaction in the meninges is a mechanism by which these peptides could produce female‐selective responses and increase the prevalence of migraine in women. ANN NEUROL 2021;89:1129–1144

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Calcitonin receptor‐like receptor (CLR), receptor activity‐modifying protein 1 (RAMP1), and calcitonin gene‐related peptide (CGRP) immunoreactivity in the rat trigeminovascular system: Differences between peripheral and central CGRP receptor distribution

Cited by 48 publications

References 0 publications

Differential distribution of calcitonin gene-related peptide and its receptor components in the human trigeminal ganglion

Differential distribution of calcitonin gene-related peptide and its receptor components in the human trigeminal ganglion

Hypersensitivity to Calcitonin Gene–Related Peptide in Post‐Traumatic Headache

Meningeal CGRP‐Prolactin Interaction Evokes Female‐Specific Migraine Behavior

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