Nitric oxide regulation of calcitonin gene‐related peptide gene expression in rat trigeminal ganglia neurons

Bellamy, Jamie; Bowen, Elizabeth J.; Russo, Andrew F.; Durham, Paul L.

doi:10.1111/j.1460-9568.2006.04742.x

Cited by 129 publications

(125 citation statements)

References 58 publications

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“…It is possible that the glial-derived NO would stimulate trigeminal neurons to increase the synthesis and release of CGRP. In support of this notion, we have previously shown that NO could stimulate CGRP promoter activity and release from cultured trigeminal ganglia neurons (Bellamy et al, 2006a). Thus, a neuron-glia inflammatory loop within the trigeminal ganglia would be established.…”

Section: Discussionmentioning

confidence: 48%

“…To determine whether RAMP1 would be expressed by glial cells maintained in vitro, primary trigeminal cultures enriched for glial cells were established using neonatal rats based on a modification of our previously published methods for studying neuronal cell function (Bellamy et al, 2006a;Bowen et al, 2006). Under our culture conditions, >95% of the cells were identified as glial cells based on cellular and nuclear morphology ( Fig.…”

Section: Glial Cells In Vivo and Maintained In Vitro Express Ramp1mentioning

confidence: 99%

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Calcitonin gene-related peptide stimulation of nitric oxide synthesis and release from trigeminal ganglion glial cells

2008

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Clinical and basic science data support an integral role of calcitonin gene-related peptide (CGRP) in migraine pathology. Following trigeminal nerve activation, afferent release of CGRP causes vasodilation while efferent release leads to pain. Although CGRP can also be secreted from cell bodies of trigeminal neurons located within the ganglion, the function of CGRP released in the ganglion is poorly understood. Initially, we showed that SNAP-25, a protein required for CGRP release, was localized in cell bodies of trigeminal ganglia neurons. We also found that satellite glial cells in the ganglia express the CGRP1 receptor protein RAMP1. To determine whether CGRP could directly activate glial cells, primary cultures of rat trigeminal ganglia were utilized to study the effects of CGRP on glial nitric oxide (NO) synthesis and release. Under our culture conditions, >95% of the cells expressed glial fibrillary acidic protein and RAMP1. While weak iNOS staining was observed in glia under basal conditions, CGRP treatment greatly increased glial iNOS expression and NO release. This stimulatory effect was blocked by the CGRP1 receptor antagonist, CGRP 8-37 peptide. Treatment of glial cultures with forskolin or cAMP also increased iNOS expression and stimulated NO release to levels similar to CGRP. To our knowledge, this is the first evidence that activation of CGRP1 receptors regulates glial iNOS and NO release. We propose that following trigeminal nerve activation, CGRP secretion from neuronal cell bodies activates satellite glial cells that release NO and initiate inflammatory events in the ganglia that contribute to peripheral sensitization in migraine.

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Section: Discussionmentioning

confidence: 48%

Section: Glial Cells In Vivo and Maintained In Vitro Express Ramp1mentioning

confidence: 99%

Calcitonin gene-related peptide stimulation of nitric oxide synthesis and release from trigeminal ganglion glial cells

2008

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“…Under our culture conditions, which are based on previously published procedures (Durham and Russo, 1999;Bellamy et al, 2006), >95% of the neurons express CGRP (Fig. 1A, 1C).…”

Section: Theobroma Cacao Extract Represses Stimulated Cgrp Secretionmentioning

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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“…[66][67][68] In vivo and in culture, iNOS was shown to augment the release of CGRP from trigeminal afferents. 69,70 However, considering the evidence for nNOS in migraine, as well as inflammatory pain studies, 26,71 it is reasonable to expect nNOS involvement in the pain pathway post-TBI. This study does not exclude nNOS as a contributor to CGRP increases or headache behavior postinjury, in which investigation is warranted.…”

Section: Trauma-induced Pain Signaling Molecules and Their Modulationmentioning

confidence: 99%

Trigeminal Pain Molecules, Allodynia, and Photosensitivity Are Pharmacologically and Genetically Modulated in a Model of Traumatic Brain Injury

Daiutolo

Tyburski

Clark

et al. 2016

Journal of Neurotrauma

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The pain-signaling molecules, nitric oxide synthase (NOS) and calcitonin gene-related peptide (CGRP), are implicated in the pathophysiology of post-traumatic headache (PTH) as they are for migraine. This study assessed the changes of inducible NOS (iNOS) and its cellular source in the trigeminal pain circuit, as well as the relationship between iNOS and CGRP after controlled cortical impact (CCI) injury in mice. The effects of a CGRP antagonist (MK8825) and sumatriptan on iNOS messenger RNA (mRNA) and protein were compared to vehicle at 2 weeks postinjury. Changes in CGRP levels in the trigeminal nucleus caudalis (TNC) in iNOS knockouts with CCI were compared to wild-type (WT) mice at 3 days and 2 weeks post injury. Trigeminal allodynia and photosensitivity were measured. MK8825 and sumatriptan increased allodynic thresholds in CCI groups compared to vehicle ( p < 0.01), whereas iNOS knockouts were not different from WT. Photosensitivity was attenuated in MK8825 mice and iNOS knockouts compared to WT ( p < 0.05). MK8825 and sumatriptan reduced levels of iNOS mRNA and iNOS immunoreactivity in the TNC and ganglia ( p < 0.01). Differences in iNOS cellular localization were found between the trigeminal ganglia and TNC. Although the knockout of iNOS attenuated CGRP at 3 days ( p < 0.05), it did not reduce CGRP at 2 weeks. CGRP immunoreactivity was found in the meningeal layers post-CCI, while negligible in controls. Findings support the importance of interactions between CGRP and iNOS in mediating allodynia, as well as the individual roles in photosensitivity. Mitigating prolonged increases in CGRP may be a promising intervention for treating acute PTH.

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Nitric oxide regulation of calcitonin gene‐related peptide gene expression in rat trigeminal ganglia neurons

Cited by 129 publications

References 58 publications

Calcitonin gene-related peptide stimulation of nitric oxide synthesis and release from trigeminal ganglion glial cells

Calcitonin gene-related peptide stimulation of nitric oxide synthesis and release from trigeminal ganglion glial cells

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

Trigeminal Pain Molecules, Allodynia, and Photosensitivity Are Pharmacologically and Genetically Modulated in a Model of Traumatic Brain Injury

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