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.

Keywords: CGRP; Piezo channels; mechanotransduction; migraine; pain.

Figure 1

Schematic presentation of the Piezo channel. (A) Bird view of the Piezo channel with peripheral blade-like structures located in three subunits forming the trimeric functional unit with the central pore, blades and anchor regions. (B) Side view of the Piezo channel located in the lipid cell membrane. The following elements of the single subunit are presented: the intracellular beams, the C-terminals with the anchor regions and the ATM region containing the Yoda1 binding site and the extracellular blades.

Figure 2

Schematic presentation of the key elements of the trigeminovascular system comprising meningeal blood vessels, local mast cells and trigeminal nerve fibers before and during migraine attack. Left: In the interictal state, before attack, there are only slight pulsations of meningeal vessels with the minimal activation of vascular Piezo1 channels or Piezo1 and Piezo2 channels in nerve fibers. Right: During migraine attack, which is often associated with brain oedema and CGRP-induced dilation of vessels, the extracellular space is reduced, promoting more close contact between pulsating vessels, nerves and nearby mast cells. The shear stress in dilated vessels and enhanced vascular pulsations promote mechanosensitive ATP release from the endothelial cells. Mechanical stimulation of calcium permeable Piezo channels in nerve fibers by pulsating vessels promotes neuronal CGRP release. CGRP and ATP can degranulate mast cells directly. In addition, the fraction of mast cells contacting vessels, is directly mechanically activated by blood pulsations. Activation of mast cells induces release of a plethora of pro-nociceptive compounds such as serotonin, histamine, leukotrienes, prostaglandins, ATP, and nitric oxide, further exciting the nociceptive fibers and promoting more CGRP release. All these pro-inflammatory compounds, in long run, together with CGRP, promote neuroinflammation, neuronal sensitization leading to long-lasting pulsating pain.