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

Abstract

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.

Cross-talk signaling in the trigeminal ganglion: role of neuropeptides and other mediators

“…This receptor channel can also be activated by volatile constituents such as umbellulone of the "headache tree" (Nassini et al 2012). Its functional role in trigeminal nociception is controversial, because on one hand there is experimental evidence for a cooperative effects with TRPV1 in meningeal afferents (Denner et al 2016) but on the other hand for a dual nociceptive-antinociceptive effect when recordings were made from spinal trigeminal neurons (Teicher et al 2017). In addition, TRP channels of the M8 type (TRPM8) are expressed in trigeminal ganglion neurons.…”

Effects of sulfide and polysulfides transmitted by direct or signal transduction‐mediated activation of TRPA1 channels

“…A functional role of HNO in elevated dura skin blood flow, as well as its effect on murine BP was demonstrated by Eberhardt and colleagues in very elegant experiments. They also detected CGRP release in response to HNO from various tissues including murine heart, mesentery, sciatic nerve and rat dura (Eberhardt et al ., ; Wild et al ., ; Dux et al ., ; Miyamoto et al ., ; Teicher et al ., ). Interaction of inorganic polysulfide with TRPA1 ion channels was examined in RIN14B, HEK293, chicken thoracic aorta epitheloid cells and murine DRG neurons.…”

TRP Channels in the Focus of Trigeminal Nociceptor Sensitization Contributing to Primary Headaches

“…TRPA1 can also be activated by volatile substances such as umbellulone of the "headache tree" [54]. Its functional role in trigeminal nociception is controversial, because there is experimental evidence for a cooperative effect with TRPV1 in meningeal afferents [55] but also for a dual nociceptive-antinociceptive effect when recordings were made from spinal trigeminal neurons [56], as discussed below in more detail (Figure 2). Another member of the TRP receptor family implicated in the migraine pathophysiology is the TRPM8 that is a cold-sensitive channel activated also by natural and synthetic "cooling" agents, such as menthol and icilin ( Figure 2).…”

“…These effects may be further modulated in afferent second order neurons. In a rat model of meningeal nociception, recordings from neurons in the spinal trigeminal nucleus with meningeal afferent input indicated that individual neurons may be activated or inhibited by the TRPA1 agonist nitroxyl (HNO, see below) [56]. Thus, the effects of TRPA1 agonists may depend on the site of action (peripheral vs. central terminals) and the functional characteristics of higher order neurons.…”