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

Abstract

Hydrogen sulfide (H2S), a well-established member of the gasotransmitter family, is involved in a variety of physiological functions, including pro-nociceptive action in the sensory system. Although several reports have shown that H2S activates sensory neurons, the molecular targets of H2S action in trigeminal (TG) nociception, implicated in migraine, remains controversial. In this study, using suction electrode recordings, we investigate the effect of the H2S donor, sodium hydrosulfide (NaHS), on nociceptive firing in rat meningeal TG nerve fibers. The effect of NaHS was also explored with patch-clamp and calcium imaging techniques on isolated TG neurons. NaHS dramatically increased the nociceptive firing in TG nerve fibers. This effect was abolished by the TRPV1 inhibitor capsazepine but was partially prevented by the TRPA1 blocker HC 030031. In a fraction of isolated TG neurons, NaHS transiently increased amplitude of capsaicin-induced currents. Moreover, NaHS by itself induced inward currents in sensory neurons, which were abolished by the TRPV1 inhibitor capsazepine suggesting involvement of TRPV1 receptors. In contrast, the inhibitor of TRPA1 receptors HC 030031 did not prevent the NaHS-induced currents. Imaging of a large population of TG neurons revealed that NaHS induced calcium transients in 41% of tested neurons. Interestingly, this effect of NaHS in some neurons was inhibited by the TRPV1 antagonist capsazepine whereas in others it was sensitive to the TRPA1 blocker HC 030031. Our data suggest that both TRPV1 and TRPA1 receptors play a role in the pro-nociceptive action of NaHS in peripheral TG nerve endings in meninges and in somas of TG neurons. We propose that activation of TRPV1 and TRPA1 receptors by H2S during neuro-inflammation conditions contributes to the nociceptive firing in primary afferents underlying migraine pain.

Protective Effects of Hydrogen Sulfide Against the ATP-Induced Meningeal Nociception

“…As we (Koroleva et al, 2017 ) and others (Roa-Coria et al, 2019 ) showed that the action of H 2 S is mediated, at least, partly by TRPV1 receptors, it could be that this inhibition is due the negative crosstalk between TRPV1 and P2X3 receptors. Thus, it has been shown previously in isolated neurons that the activation of TRPV1 receptors decreased the subsequent activation of ATP-gated P2X3 receptors (Stanchev et al, 2009 ).…”

“…The main finding of this study is that in meninges, the gaseous transmitter H 2 S exerts the multicomponent protecting action against the powerful nociceptive agent, extracellular ATP. This finding is unusual as H 2 S can itself transiently promote nociceptive firing in trigeminal afferents (Koroleva et al, 2017 ).…”

“…Recently, we showed that the H 2 S donor NaHS can trigger nociceptive firing in rat trigeminal afferents (Koroleva et al, 2017 ). However, this pro-nociceptive effect was transient as the firing quickly returned to the baseline level in the presence of H 2 S.…”

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

“…A relatively recent publication detected activation of TRPV1 channels in rat TRG neurons by NaHS based on inhibition by capsazepine. However, the majority of investigators in the sulfide field consider the gasotransmitter as selective for TRPA1 channels and evidence for activation of TRPV1 channels is scarce (Trevisani et al ., ; Ang et al ., ; Medeiros et al ., ; Lu et al ., ; Koroleva et al ., ; Yu et al ., ). No individual excitatory action but potentiation of the capsaicin‐induced response by NaHS was reported in isolated vagal neurons from rat lungs .…”

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

“…Hydrogen sulfide (H 2 S) and NO, members of the gasotransmitter family, are involved in the regulation of a great variety of physiological functions, including cardiovascular functions, nociception and inflammation [149,150]. A substantial body of evidence indicates that H 2 S increases the firing rate of trigeminal ganglion neurons by acting on TRP receptors [56,151]. H 2 S is synthesized from cysteine through several enzymatic pathways.…”