Capsaicin-Sensitive Sensory Nerves Mediate the Cellular and Microvascular Effects of H2S via TRPA1 Receptor Activation and Neuropeptide Release

Abstract

It is supposed that TRPA1 receptor can be activated by hydrogen sulphide (H2S). Here, we have investigated the role of TRPA1 receptor in H2S-induced [Ca(2+)]i increase in trigeminal ganglia (TRG) neurons, and the involvement of capsaicin-sensitive sensory nerves in H2S-evoked cutaneous vasodilatation. [Ca(2+)]i was measured with ratiometric technique on TRG neurons of TRPA1(+/+) and TRPA1(-/-) mice after NaHS, Na2S, allylisothiocyanate (AITC) or KCl treatment. Microcirculatory changes in the ear were detected by laser Doppler imaging in response to topical NaHS, AITC, NaOH, NaSO3 or NaCl. Mice were either treated with resiniferatoxin (RTX), or CGRP antagonist BIBN4096, or NK1 receptor antagonist CP99994, or K(+) ATP channel blocker glibenclamide. Alpha-CGRP(-/-) and NK1 (-/-) mice were also investigated. NaHS and Na2S increased [Ca(2+)]i in TRG neurons derived from TRPA(+/+) but not from TRPA1(-/-) mice. NaHS increased cutaneous blood flow, while NaOH, NaSO3 and NaCl did not cause significant changes. NaHS-induced vasodilatation was reduced in RTX-treated animals, as well as by pre-treatment with BIBN4096 or CP99994 alone or in combination. NaHS-induced vasodilatation was significantly smaller in alpha-CGRP(-/-) or NK1 (-/-) mice compared to wild-types. H2S activates capsaicin-sensitive sensory nerves through TRPA1 receptors and the resultant vasodilatation is mediated by the release of vasoactive sensory neuropeptides CGRP and substance P.

Receptor Mechanisms Mediating the Pro-Nociceptive Action of Hydrogen Sulfide in Rat Trigeminal Neurons and Meningeal Afferents

“…As previous studies suggested the action of NaHS in different tissues could be mediated either by TRPV1 or TRPA1 receptors (Trevisani et al, 2005; Andersson et al, 2012; Okubo et al, 2012; Lu et al, 2014; Hajna et al, 2016), we next examined the pro-nociceptive effect of NaHS in the presence of the specific inhibitors of these receptors. Inhibition of TRPV1 receptors by capsazepine (25 μM) did not significantly change TG nerve firing (0.40 ± 0.11 s −1 in control, vs. 0.32 ± 0.13 s −1 in capsazepine; n = 6, p = 0.14).…”

“…However, 20% of H 2 S induced Ca 2+ transients were also abolished by HC 030031 indicating the activation of TRPA1 receptors in a small fraction of neurons, which was supported by a number of other studies. It was shown that in TG neurons application of NaHS increased [Ca 2+ ] in in 20–42% of capsaicin-sensitive neurons with close correspondence between neurons that responded to NaHS and to AITC (Hajna et al, 2016). NaHS also evoked inward currents in DRG neurons and in CHO cells expressing TRPA1 receptors, which were inhibited by a TRPA1 antagonist (Miyamoto et al, 2011; Andersson et al, 2012; Ogawa et al, 2012).…”

“…In the guinea-pig and human colon H 2 S caused mucosal Cl − secretion (Schicho et al, 2006) and increased afferent firing in rat intestinal mesenteric nerves by activation of TRPV1 in afferent endings (Lu et al, 2014). On the other hand activation of TRPA1 by NaHS in afferent nerve fibers was reported to mediate an increased cutaneous blood flow by the release of CGRP and substance P in the mouse ear model (Hajna et al, 2016), whereas vasodilatory effects of H 2 S were reduced in mice lacking TRPA1 receptors (Pozsgai et al, 2012). …”

“…However, there is also evidence indicating activation of TRPA1 receptors by H 2 S. Activation of capsaicin-sensitive sensory nerves through TRPA1 receptors by NaHS-induced vasodilatation resulting from the release of the vasoactive neuropeptides calcitonin gene-related peptide (CGRP) and substance P (Pozsgai et al, 2012; Hajna et al, 2016). Indirect evidence shows that activation of TRPA1 channels by H 2 S resulted in mechanical hyperalgesia and allodynia in mice (Okubo et al, 2012) whereas TRPA1 did not participate in pro-nociceptive effects of H 2 S in visceral tissues (Andersson et al, 2012).…”

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

“…Vasodilator effects of H 2 S were decreased in TRPA1 knockout (TRPA1 −/− ) mice or in wild‐type mice after treatment with HC030031 (Pozsgai et al ., ), indicating a primary role of TRPA1 channels in mediating the vascular effects of H 2 S in the skin. Activation of TRPA1 receptors by sulfide‐released CGRP with consequent vasodilation (Pozsgai et al ., ; Eberhardt et al ., ; Hajna et al ., ).…”