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

Kseniya Koroleva,Anton Hermann,Aleksey Yakovlev,Rashid Giniatullin,Guzel Sitdikova,Alsu Mustafina

doi:10.3389/fncel.2017.00226

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.

Highlights

Hydrogen sulfide (H2S), a member of the gasotransmitter family along with nitric oxide (NO) and carbon monoxide, is involved in the regulation of great variety of physiological functions, including nociception and inflammation (Kawabata et al, 2007; Feng et al, 2013)
We propose that activation of TRPV1 and TRPA1 receptors by hydrogen sulfide (H2S) during neuro-inflammation conditions contributes to the nociceptive firing in primary afferents underlying migraine pain
As previous studies suggested the action of sodium hydrosulfide (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 examined the pro-nociceptive effect of NaHS in the presence of the specific inhibitors of these receptors

Summary

Introduction

Hydrogen sulfide (H2S), a member of the gasotransmitter family along with nitric oxide (NO) and carbon monoxide, is involved in the regulation of great variety of physiological functions, including nociception and inflammation (Kawabata et al, 2007; Feng et al, 2013). The neuro-modulatory role of H2S was shown in the central and peripheral nervous system where it promotes the induction of long-term potentiation (LTP) in hippocampus (Abe and Kimura, 1996), inhibits giant depolarizing potentials in neonatal hippocampus (Yakovlev et al, 2017), affects NMDA-mediated currents (Abe and Kimura, 1996; Yakovlev et al, 2017), increases the transmitter release from motor nerve endings (Sitdikova et al, 2011; Gerasimova et al, 2013, 2015), or initiates contractile responses of the rat urinary bladder by stimulation of primary afferent neurons (Patacchini et al, 2004). Intracolonical administration of sodium hydrosulfide (NaHS), a H2S donor, induced nociceptive behavior with abdominal hyperalgesia/allodynia (Matsunami et al, 2009). NaHS produced mechanical hyperalgesia in the rat hind paw in response to intraplantar administration (Kawabata et al, 2007). NaHS activates ATP-dependent K+ channels in different tissues (Tang et al, 2005; Mustafina et al, 2015) which may underlie the antinociceptive effects of NaHS (Distrutti et al, 2006)

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