Neurogasobiology of migraine: Carbon monoxide, hydrogen sulfide, and nitric oxide as emerging pathophysiological trinacrium relevant to nociception regulation.

BACKGROUND

Nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H₂S) are bioactive gasotransmitters implicated in migraine pathophysiology. These gases regulate vascular tone, nociceptive transmission, and inflammatory pathways, playing key roles in both the onset and modulation of migraine.

METHODS

This review synthesizes current evidence on the role of NO, CO, and H₂S in migraine, focusing on their molecular mechanisms, interactions, and potential therapeutic implications. Data from human and animal studies were analyzed to elucidate their contributions to migraine pathogenesis.

RESULTS

NO is a well-established migraine trigger, with NO donors such as nitroglycerin inducing headache and migraine attacks via cyclic guanosine monophosphate (cGMP)-dependent pathways. CO interacts with NO and cGMP signaling in pain modulation, contributing to central and peripheral nociceptive processing. H₂S exerts dual effects: while its interaction with NO forms nitroxyl (HNO), activating transient receptor potential ankyrin 1 (TRPA1) channels and triggering calcitonin gene-related peptide (CGRP) release; it also demonstrates neuroprotective properties through antioxidant mechanisms and nuclear factor erythroid 2-related factor 2 (Nrf2) activation. Additionally, epigenetic modifications of calcitonin gene-related peptide alpha (CALCA) have been implicated in migraine susceptibility, further supporting the role of these gasotransmitters in disease pathology.

CONCLUSION

The interplay between NO, CO, and H₂S represents a critical aspect of migraine pathophysiology, influencing vascular, inflammatory, and nociceptive pathways. Understanding these gasotransmitters' roles may provide novel therapeutic targets for migraine management, particularly through modulation of TRPA1-CGRP signaling and oxidative stress pathways. Further research is warranted to explore their clinical applications in migraine treatment.