Abstract
We previously showed that extracellular ATP and hydrogen sulfide (H2S), a recently discovered gasotransmitter, are both triggering the nociceptive firing in trigeminal nociceptors implicated in migraine pain. ATP contributes to meningeal nociception by activating the P2X3 subunit-containing receptors whereas H2S operates mainly via TRP receptors. However, H2S was also proposed as a neuroprotective and anti-nociceptive agent. This study aimed to test the effect of H2S on ATP-mediated nociceptive responses in rat meningeal afferents and trigeminal neurons and on ATP-induced degranulation of dural mast cells. Electrophysiological recording of trigeminal nerve activity in meninges was supplemented by patch-clamp and calcium imaging studies of isolated trigeminal neurons. The H2S donor NaHS induced a mild activation of afferents and fully suppressed the subsequent ATP-induced firing of meningeal trigeminal nerve fibers. This anti-nociceptive effect of H2S was specific as an even stronger effect of capsaicin did not abolish the action of ATP. In isolated trigeminal neurons, NaHS decreased the inward currents and calcium transients evoked by activation of ATP-gated P2X3 receptors. Moreover, NaHS prevented ATP-induced P2X7 receptor-mediated degranulation of meningeal mast cells which emerged as triggers of migraine pain. Finally, NaHS decreased the concentration of extracellular ATP in the meningeal preparation. Thus, H2S exerted the multiple protective actions against the nociceptive effects of ATP. These data highlight the novel pathways to reduce purinergic mechanisms of migraine with pharmacological donors or by stimulation production of endogenous H2S.
Highlights
Long-lasting migraine pain likely originating from meninges, involves local inflammation, sensitization and activation of trigeminal afferents by multiple endogenous compounds released from local vessels, somatic and parasympathetic nerves and various immune cells such as mast cells occupying this area (Bolay et al, 2002; Levy et al, 2007; Olesen et al, 2009; Burstein et al, 2015; Koroleva et al, 2019)
We analyzed the crosstalk in signaling between two endogenous messengers ATP and H2S in the rat trigeminal system implicated in migraine pain
We demonstrated here that H2S prevented ATP-induced activation of the trigeminal nerve fibers showing the anti-nociceptive effect
Summary
Long-lasting migraine pain likely originating from meninges, involves local inflammation, sensitization and activation of trigeminal afferents by multiple endogenous compounds released from local vessels, somatic and parasympathetic nerves and various immune cells such as mast cells occupying this area (Bolay et al, 2002; Levy et al, 2007; Olesen et al, 2009; Burstein et al, 2015; Koroleva et al, 2019). H2S Protects Against ATP-Induced Nociception or gaseous transmitter nitric oxide (NO) promoting pain and dilating cortical vessels (Reuter et al, 2001; Pryazhnikov et al, 2014; Messlinger et al, 2020). Hydrogen sulfide (H2S) is a common gaseous transmitter that regulates many physiological and pathological processes (Kimura, 2011; Hermann et al, 2012; Wang, 2012; Paul and Snyder, 2018). H2S is generated from sulfur-containing amino acids, primarily L-cysteine and L-homocysteine by the enzymes cystathionine-β-synthase (CBS), cystathionine-γ-lyase (CSE) and 3-mercaptopyruvate sulfurtransferase (Kimura, 2011; Hermann et al, 2012; Wang, 2012; Paul and Snyder, 2018). CBS is the main enzyme for the synthesis of H2S in the nervous tissue, whereas, in the cardiovascular system, liver, and kidneys, the main synthesis enzyme for H2S is CSE (Kimura, 2011)
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