Increase in CGRP- and nNOS-immunoreactive neurons in the rat trigeminal ganglion after infusion of an NO donor

Dieterle, Anne; Fischer, Michael J.M.; Link, Andrea; Neuhuber, Winfried; Meßlinger, Karl

doi:10.1177/0333102410375725

Cited by 48 publications

(46 citation statements)

References 69 publications

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“…Several other signaling molecules have been found in the trigeminal ganglion, these include substance P, neurokinin A, dynorphine, nitric oxide and PACAP (Tajti et al, 1999;Hou et al, 2001;Dieterle et al, 2011). Yet clearly there may be many other contributing neuropeptides that could act in concert with CGRP.…”

Section: Discussionmentioning

confidence: 99%

Localization of CGRP, CGRP receptor, PACAP and glutamate in trigeminal ganglion. Relation to the blood–brain barrier

et al. 2015

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Section: Discussionmentioning

confidence: 99%

Localization of CGRP, CGRP receptor, PACAP and glutamate in trigeminal ganglion. Relation to the blood–brain barrier

et al. 2015

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“…The delayed effect of NO on central trigeminal activity may be associated with the expression or availability of CGRP and NO synthase in the trigeminal ganglion or ophthalmic region (47). Thus, NO may have different effects with differing time-course, i.e., an acute effect already occurring during infusion followed by a subacute effect of increased neuronal activity within the next 20 min and a late effect appearing as upregulation of proteins like CGRP, CGRP receptors, and NO synthase some hours after infusion of NO donors (47, 48).…”

Section: Discussionmentioning

confidence: 99%

Hydrogen Sulfide Mediating both Excitatory and Inhibitory Effects in a Rat Model of Meningeal Nociception and Headache Generation

2017

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Background/purposeHydrogen sulfide (H2S) is a neuromodulator acting through nitroxyl (HNO) when it reacts with nitric oxide (NO). HNO activates transient receptor potential channels of the ankyrin type 1 (TRPA1) causing release of calcitonin gene-related peptide from primary afferents. Activation of meningeal nociceptors projecting to the human spinal trigeminal nucleus (STN) may lead to headaches. In a rat model of meningeal nociception, the activity of spinal trigeminal neurons was used as read-out for the interaction between H2S and NO.MethodsIn anesthetized rats extracellular recordings from single neurons in the STN were made. Sodium sulfide (Na2S) producing H2S in the tissue and the NO donor diethylamine-NONOate (DEA-NONOate) were infused intravenously. H2S was also locally applied onto the exposed cranial dura mater or the medulla. Endogenous production of H2S was inhibited by oxamic acid, and NO production was inhibited by nitro-l-arginine methyl ester hydrochloride (l-NAME) to manipulate endogenous HNO formation.Key resultsSystemic administration of Na2S was followed either by increased ongoing activity (in 73%) or decreased activity (in 27% of units). Topical application of Na2S onto the cranial dura mater caused a short-lasting activation followed by a long-lasting decrease in activity in the majority of units (70%). Systemic administration of DEA-NONOate increased neuronal activity, subsequent infusion of Na2S added to this effect, whereas DEA-NONOate did not augment the activity after Na2S. The stimulating effect of DEA-NONOate was inhibited by oxamic acid in 75% of units, and l-NAME following Na2S administration returned the activity to baseline.ConclusionIndividual spinal trigeminal neurons may be activated or (less frequently) inhibited by the TRPA1 agonist HNO, presumably formed by H2S and NO in the STN, whereby endogenous H2S production seems to be rate-limiting. Activation of meningeal afferents by HNO may induce decreased spinal trigeminal activity, consistent with the elevation of the electrical threshold caused by TRPA1 activation in afferent fibers. Thus, the effects of H2S–NO–TRPA1 signaling depend on the site of action and the type of central neurons. The role of H2S–NO–TRPA1 in headache generation seems to be ambiguous.

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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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Increase in CGRP- and nNOS-immunoreactive neurons in the rat trigeminal ganglion after infusion of an NO donor

Cited by 48 publications

References 69 publications

Localization of CGRP, CGRP receptor, PACAP and glutamate in trigeminal ganglion. Relation to the blood–brain barrier

Localization of CGRP, CGRP receptor, PACAP and glutamate in trigeminal ganglion. Relation to the blood–brain barrier

Hydrogen Sulfide Mediating both Excitatory and Inhibitory Effects in a Rat Model of Meningeal Nociception and Headache Generation

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

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