The Emerging Role of Mechanosensitive Piezo Channels in Migraine Pain

Abstract

Recently discovered mechanosensitive Piezo channels emerged as the main molecular detectors of mechanical forces. The functions of Piezo channels range from detection of touch and pain, to control of the plastic changes in different organs. Recent studies suggested the role of Piezo channels in migraine pain, which is supposed to originate from the trigeminovascular nociceptive system in meninges. Interestingly, migraine pain is associated with such phenomenon as mechanical hypersensitivity, suggesting enhanced mechanotransduction. In the current review, we present the data that propose the implication of Piezo channels in migraine pain, which has a distinctive pulsatile character. These data include: (i) distribution of Piezo channels in the key elements of the trigeminovascular nociceptive system; (ii) the prolonged functional activity of Piezo channels in meningeal afferents providing a mechanistical basis for mechanotransduction in nociceptive nerve terminals; (iii) potential activation of Piezo channels by shear stress and pulsating blood flow; and (iv) modulation of these channels by emerging chemical agonists and modulators, including pro-nociceptive compounds. Achievements in this quickly expanding field should open a new road for efficient control of Piezo-related diseases including migraine and chronic pain.

Antidromic Spike Propagation and Dissimilar Expression of P2X, 5-HT, and TRPV1 Channels in Peripheral vs. Central Sensory Axons in Meninges

“…These immune cells can release a plethora of pro-nociceptive transmitters including 5-HT (Kilinc et al, 2017 ), which can amplify the action of classical algogen ATP, acting via neuronal 5-HT3 receptors at nerve terminals (Koroleva et al, 2019 ; Suleimanova et al, 2020 ). In turn, release of ATP could be amplified by mechanical forces from pulsating meningeal vessels acting via neuronal or vascular Piezo channels (Cinar et al, 2015 ; Wang et al, 2016 ), further contributing to meningeal nociception (Mikhailov et al, 2019 ; Della Pietra et al, 2020 ; Suleimanova et al, 2020 ). The crosstalk between various pro-nociceptive factors in the receptive field of meninges around MMA can explain our current observation on why the peripheral parts of the trigeminal nerve are more effective nociceptive devices.…”

“…Moreover, during inflammation, GABAergic PAD (proposed as generator of antidromic activity) is increased (Willis, 1999 ; Lin et al, 2007 ), leading to enhanced orthodromic spiking (Takkala et al, 2016 ). These non-canonical GABAergic excitatory mechanism along with increased intra-ganglion crosstalk between neurons and glia could result in migraine-related peripheral effects in the meninges such as enhanced CGRP release, vasodilation, mast cell degranulation, and associated local sterile inflammation (Messlinger, 2009 ; Della Pietra et al, 2020 ).…”

Modeling a Nociceptive Neuro-Immune Synapse Activated by ATP and 5-HT in Meninges: Novel Clues on Transduction of Chemical Signals Into Persistent or Rhythmic Neuronal Firing

“…Migraine pain has a still unexplained pulsating character perhaps due to mechanical fluctuations of meningeal vessels (Mikhailov et al, 2019;Della Pietra et al, 2020) that might interact with nearby nerve fibers and mast cells (Figures 1Ab; 6A). In order to investigate the potential role of pulsating blood flow as a trigger of meningeal nociception and its relation to ATP-and 5-HT-induced firing, we hypothesized that vasodilation (during migraine attacks) of pulsating meningeal vessels can stimulate release of these two mediators from local mast cells.…”

Distinct Activity of Endocannabinoid-Hydrolyzing Enzymes MAGL and FAAH in Key Regions of Peripheral and Central Nervous System Implicated in Migraine

“…However, it has been shown that the potential trigger for migraine attack is psychogenic stress, which can precipitate or worsen migraine [ 28 , 29 ]. Such stress can promote the release of corticotropin-releasing hormone [ 29 ], directly activating meningeal mast cells that are closely interacting with the dural nerves in the TGVS [ 30 , 31 , 32 ]. Alternatively, stress can provoke sleep disturbances, also known to trigger migraine episodes [ 33 , 34 ].…”