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

BACKGROUND/PURPOSE: Hydrogen sulfide (H(2)S) 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 H(2)S and NO. METHODS: In anesthetized rats extracellular recordings from single neurons in the STN were made. Sodium sulfide (Na(2)S) producing H(2)S in the tissue and the NO donor diethylamine-NONOate (DEA-NONOate) were infused intravenously. H(2)S was also locally applied onto the exposed cranial dura mater or the medulla. Endogenous production of H(2)S 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 RESULTS: Systemic administration of Na(2)S was followed either by increased ongoing activity (in 73%) or decreased activity (in 27% of units). Topical application of Na(2)S 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 Na(2)S added to this effect, whereas DEA-NONOate did not augment the activity after Na(2)S. The stimulating effect of DEA-NONOate was inhibited by oxamic acid in 75% of units, and l-NAME following Na(2)S administration returned the activity to baseline. CONCLUSION: Individual spinal trigeminal neurons may be activated or (less frequently) inhibited by the TRPA1 agonist HNO, presumably formed by H(2)S and NO in the STN, whereby endogenous H(2)S 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 H(2)S–NO–TRPA1 signaling depend on the site of action and the type of central neurons. The role of H(2)S–NO–TRPA1 in headache generation seems to be ambiguous.