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Hydrogen sulfide suppresses pain signals in migraine

Extracellular ATP is a powerful trigger of migraine, but the endogenous gaseous transmitter hydrogen sulfide known by its unpleasant smell prevents ATP-induced nociception, according to the doctoral thesis of Kseniia Koroleva. Thus, the promotion of hydrogen sulfide synthesis could offer a new approach to the treatment of migraine.

Peripheral mechanisms of primary headaches such as cluster headache and migraine remain unclear. Multiple studies assign the leading role in the generation of a pain signal to the trigeminovascular system. According to the purinergic theory of migraine, extracellular ATP released in the trigeminovascular system from the endothelium, mast cells, platelets and other meningeal cells plays one of the leading roles in migraine pathology and in pain transmission. However, the molecular mechanisms of ATP action in meninges are still not fully understood. Hydrogen sulfide (H2S) is a recently discovered gasotransmitter the role of which in  pain signaling has been little studied. In particular, the role of H2S in meningeal nociception and its action on ATP-mediated pain signaling has not been investigated. Thus, the main objectives of the present study were to analyze the novel cellular and receptors mechanisms of meningeal nociception induced by ATP and its interactions with the signaling pathways activated by the gaseous transmitter H2S.

The first novel finding of the study was  that ATP induced the nociceptive activity both in rat and mouse trigeminal nerves in meninges, an origin site of migraine pain. To put it simply, increased "nociceptive activity" is an indication of more intense migraine pain. Using mice lacking mast cells, the researchers discovered that ATP-induced nociceptive activity essentially depends on degranulation of dural mast cells with subsequent release of serotonin which amplifies the excitatory effect of ATP.

Second, H2S was shown to have a weak and short-lasting excitatory action on trigeminal neurons via TRP type channels.

Third, the pre-application of the H2S donor was found to suppress the nociceptive effect of ATP in the trigeminovascular system indicating the anti-nociceptive action of this gaseous transmitter.  In addition, H2S reduced the ATP levels in the meninges and prevented ATP-induced mast cell degranulation. These data indicate a novel multicomponent pain-preventing role of H2S, which is expected to be especially pronounced in conditions of neuroinflammation associated with enhanced release of ATP. The promotion of H2S synthesis within the trigeminovascular system, might, therefore, be a novel therapeutic approach for the treatment or prevention of migraine pain.

The doctoral thesis of Kseniia Koroleva, entitled The mechanisms of ATP and hydrogen sulfide action on the trigeminal system of rat and mouse will be examined at the Faculty of Health Sciences. The public examination will take place in Kazan Federal University, Kazan, Russia and streamed online on September 23, 2020. The opponents in the public examination will be Professor Petr Masliukov of the Yaroslavl State Medical University and Dr. Alexander Gaydukov of the Moscow State University. The Custos will be Professor Guzel Sitdikova of the Kazan Federal University and Professor Rashid Giniatullin of the University of Eastern Finland.

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Link to the dissertation