Gasotransmitters (NO, H2S, CO) as Contributors to the Nociceptive Process in the Trigeminovascular System

Gasotransmitters (gas-mediators) such as nitric oxide (NO), hydrogen sulfide (H2S) and carbon monoxide (CO) are a promising group of endogenous signaling molecules to study. The physiological effects of gasotransmitters may contribute to the generation of nociceptive signal in various pain syndromes, including migraine. The basis of pain sensation in migraine is the activation of the trigeminovascular system (TVS), consisting of trigeminal ganglion (TG) afferents, blood vessels and mast cells in the dura mater. The involvement of NO in the nociceptive signaling process in headaches has been described in numerous studies, and injections of the NO donor, nitroglycerin, are a well-known method for modelling migraine in humans and laboratory animals. In TVS, NO interacts with various molecular targets such as TRPV1 and TRPA1 channels, as well as key migraine mediators, PACAP (pituitary adenylate cyclase-activating polypeptide) and CGRP (сalcitonin gene-related peptide). H2S exerts its own activating effect on trigeminal nerve activity and is also able to modulate the activity of TRP channels (transient receptor potential channels) and P2X receptors, exhibiting both pro- and antinociceptive effects. The result of the interaction between NO and H2S, nitroxyl ion (HNO-) is able to activate TRPA1 channels. CO is a less studied gasotransmitter in the context of molecular mechanisms of migraine, but the involvement of its producing enzyme, haemoxygenase, in pro- and anti-nociceptive effects in models of inflammatory and neuropathic pain has been described. The molecular targets of CO action remain unidentified in TVS. This review provides information on the role of endogenous and exogenous gasotransmitters in TVS, in which the excitability of peripheral afferents determines the occurrence of action potentials that transmit the nociceptive signal to central structures, and sensitization is a factor in the development of chronic migraine. An in-depth study of the signaling role of gasotransmitters in the pathophysiology of migraine pain syndrome may contribute to the development of more effective therapies for this pathology.