Exploring the epigenetic modifications of the RONS-TRPA1-CGRP axis in migraine pathophysiology

Epigenetic studies in migraine provided results on the occurrence or lack of epigenetic modifications of genes whose products are important in migraine pathogenesis. However, these studies focus on single genes without analyzing how epigenetic modifications can affect complex signaling pathways. This narrative/hypothesis review aims to provide information on how the reactive oxygen and nitrogen species (RONS)-transient receptor potential cation channel subfamily A member 1 (TRPA1)-calcitonin gene-related peptide (CGRP) axis functions, suggesting that its epigenetic modifications could be a significant factor in migraine pathophysiology.

Oxidative stress is both a cause and a consequence of migraine, and reactive oxygen and nitrogen species (RONS), like other noxious stimuli, may activate the transient receptor potential cation channel subfamily A member 1 (TRPA1) to send pain signals. Methylation of the TRPA1 gene correlates with various pain states; however, the results of these studies are largely inconsistent. DNA methylation and the action of non-coding RNAs are important in the alternative RNA processing of the calcitonin-related polypeptide alpha (CALCA) gene and its transcript to produce calcitonin gene-related peptide (CGRP). The release of CGRP and substance P from trigeminal neuron terminals, mediated by TRPA1 activation and involving mitogen-activated protein kinase 1/2, is a primary mechanism driving migraine headaches. Epigenetic memory may be related to neural plasticity and migraine chronification. Therefore, the RONS-TRPA1-CGRP signaling pathways may be important in migraine pathogenesis, as demonstrated in experimental animals by the phenomenon of cortical spreading depolarization.

The RONS-TRPA1-CGRP axis plays a significant role in the pathogenesis of migraine and other pain-related syndromes. Epigenetic modifications of the genes encoding the components of the antioxidant defense system, TRPA1 and CGRP, are crucial in migraine pathogenesis, prevention, and therapy. However, due to the sequence specificity of the axis, only non-coding RNAs can currently be considered for therapeutic intervention in migraine, targeting the epigenetic profile of the RONS-TRPA1-CGRP axis.