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Supplemental material, sj-pdf-1-cep-10.1177_0333102421989261 for TRESK background potassium channel modifies the TRPV1-mediated nociceptor excitability in sensory neurons by Miklós Lengyel, Dominika Hajdu, Alice Dobolyi, Judit Rosta, Gábor Czirják, Mária Dux and Péter Enyedi in Cephalalgia

Seit Langem ist bekannt, dass Kopfschmerzen durch nozizeptive Vorgange in der harten Hirnhaut (Dura mater encephali) und an grosen zerebralen Arterien entstehen konnen, da die experimentelle Reizung dieser Strukturen zu Kopfschmerzempfindungen fuhrt. Daneben sind am Kopfschmerzgeschehen wahrscheinlich auch extrakraniale Strukturen wie die Kopf- und Halsmuskulatur mit ihren Triggerpunkten beteiligt. Dieser Zusammenhang wurde bisher in erster Linie durch eine konvergente Verschaltung primarer nozizeptiver Afferenzen auf sekundare Neurone im trigemino-zervikalen Hirnstammkomplex erklart. Durch sog. Tracing-Experimente an Schadelkalotten von Nagern und dem Menschen sowie funktionelle Untersuchungen gibt es allerdings klare Hinweise auf Nervenfasern der Dura mater, die mit Kollateralen durch Suturen und Venenkanale den Schadelknochen verlassen und das Periost sowie tiefe Schichten der Kopfmuskulatur innervieren konnen. Uber diese extrakranialen Kollateralen werden vermutlich die Erregungsvorgange an den meningealen Afferenzen und somit das Kopfschmerzgeschehen moduliert. Moglicherweise ist dies auch einer der Wege, auf dem Kopfschmerzen durch unterschiedlichste extrakraniale Manipulationen therapeutisch beeinflusst werden konnen.

BACKGROUND AND PURPOSE: Meningeal blood flow is controlled by calcitonin gene-related peptide (CGRP) released from trigeminal afferents and nitric oxide (NO) mainly produced in arterial endothelium. The vasodilatory effect of NO may be due to the NO sibling nitroxyl (HNO), generated through the reaction with hydrogen sulfide (H2 S). We investigated the involvement of HNO in CGRP release and meningeal blood flow. EXPERIMENTAL APPROACH: Blood flow in the exposed rat dura mater was recorded by laser Doppler flowmetry. CGRP release from the dura mater in the hemisected rat head was quantified using an ELISA. NO and H2 S were localised histochemically with specific sensors. KEY RESULTS: Topical administration of the NO donor diethylamine-NONOate increased meningeal blood flow by 30%. Preadministration of oxamic acid, an inhibitor of H2 S synthesis, reduced this effect. Administration of Na2 S increased the flow by 20%. This effect was abolished by the CGRP receptor antagonist CGRP8-37 or the TRPA1 antagonist HC030031 and reduced when endogenous NO synthesis was blocked. Na2 S dose-dependently increased CGRP release 2-3-fold. Co-administration of diethylamine-NONOate facilitated CGRP release, while inhibition of endogenous NO or H2 S synthesis lowered basal CGRP release. NO and H2 S were mainly localised in arterial vessels, HNO additionally in nerve fibre bundles. HNO staining was lost after the treatment with L-NMMA and oxamic acid. CONCLUSIONS AND IMPLICATIONS: NO and H2 S cooperatively increase meningeal blood flow by forming HNO, which activates TRPA1 receptor channels of trigeminal fibres inducing CGRP release. The proposed role of the HNO-TRPA1-CGRP signalling for the pathophysiology of headaches is discussed.

1. Vasodilatation in the dura mater has been suggested to play an important role in the pathophysiology of vascular headaches. Histamine may contribute to these vascular changes. The aim of the present study was to examine the role of different histamine receptors in histamine-induced meningeal hyperperfusion using laser Doppler flowmetry. 2. The blood flow in the medial meningeal artery was monitored in the exposed parietal dura mater encephali of barbiturate anaesthetized rats. Local application of histamine (10(-5) and 10(-4) M) onto the dura caused increases in flow to 114.2+/-9.6 and 135.1+/-19.1%, respectively, of the basal flow. 3. Flow increases induced by topical application of histamine (10(-4) M) were reduced by local pretreatment with the H(2)-receptor antagonist cimetidine (0.4 and 4 mM) to 63.4+/-17 and 37.8+/-18.8%, respectively. Systemic pre-administration of cimetidine (5 mg kg(-1) i.v.) did not change histamine-induced flow increases. 4. Local pretreatment with the H(1)-receptor antagonist cetirizine (2 micro M) further increased the flow evoked by topical histamine administration (10(-4) M) to 123.5+/-14.7% of the histamine control. 5. Increases in blood flow induced by i.v. administration of histamine (10 micro g kg(-1)) were reduced by i.v. pre-injection of cetirizine (50 micro g kg(-1)) to 31.9+/-9% but not by i.v. cimetidine (5 mg kg(-1)). 6. We conclude that histamine-induced relaxation of dural arterial vessels is mediated by H(2)-receptors, most likely located on vascular smooth muscle cells, and by endothelial H(1)-receptors. In addition, H(1)-receptors on smooth muscle cells may mediate vasoconstriction.