Piezo channels in peripheral trigeminal nociception

Mechanical pain, as a unique sensory modality, has been speculated to be mechanistically associated with either Piezo1 or Piezo2 channels, provided they are expressed in the neurons responsible for somatic and visceral pain. It has been shown that the administration of piezo channel agonists such as Yoda1 leads to the subsequent activation of mouse Piezo1 (mPiezo1). As a result of Yoda1 administration, the trigeminal nerve fibers remain activated for a longer duration. The novel Jedi1/2 also like the Yoda1 possesses specificity toward the Piezo1 channel. Piezo channel antagonists are of particular relevance because they possess the ability to mitigate the excessive activation of nociceptors which contributes to migraines. Piezo channels deviate significantly in the sequence of their amino acids and structural composition from other mechanosensitive channels. This distinguishing feature positions Piezo channels as an entirely novel molecular target for several therapeutic approaches. The possibility of attaining analgesic effects in migraine pain can be embarked on either through the targeted delivery of novel potent Piezo blockers to the trigeminovascular system or by inactivating these mechanotransducers via agents that exert their influence through modifications in the lipophilic environment of the neuronal membrane.