Epigenetic Connections of the TRPA1 Ion Channel in Pain Transmission and Neurogenic Inflammation — a Therapeutic Perspective in Migraine?

Persistent reprogramming of epigenetic pattern leads to changes in gene expression observed in many neurological disorders. Transient receptor potential cation channel subfamily A member 1 (TRPA1), a member of the TRP channels superfamily, is activated by many migraine triggers and expressed in trigeminal neurons and brain regions that are important in migraine pathogenesis. TRP channels change noxious stimuli into pain signals with the involvement of epigenetic regulation. The expression of the TRPA1 encoding gene, TRPA1, is modulated in pain-related syndromes by epigenetic alterations, including DNA methylation, histone modifications, and effects of non-coding RNAs: micro RNAs (miRNAs), long non-coding RNAs, and circular RNAs. TRPA1 may change epigenetic profile of many pain-related genes as it may modify enzymes responsible for epigenetic modifications and expression of non-coding RNAs. TRPA1 may induce the release of calcitonin gene related peptide (CGRP), from trigeminal neurons and dural tissue. Therefore, epigenetic regulation of TRPA1 may play a role in efficacy and safety of anti-migraine therapies targeting TRP channels and CGRP. TRPA1 is also involved in neurogenic inflammation, important in migraine pathogenesis. The fundamental role of TRPA1 in inflammatory pain transmission may be epigenetically regulated. In conclusion, epigenetic connections of TRPA1 may play a role in efficacy and safety of anti-migraine therapy targeting TRP channels or CGRP and they should be further explored for efficient and safe antimigraine treatment. This narrative/perspective review presents information on the structure and functions of TRPA1 as well as role of its epigenetic connections in pain transmission and potential in migraine therapy.