Mechanosensitive meningeal nociception via Piezo channels: Implications for pulsatile pain in migraine?. (1st May 2019)

• Record Type: Journal Article
• Authors: Mikhailov, Nikita; Leskinen, Jarkko; Fagerlund, Ilkka; Poguzhelskaya, Ekaterina; Giniatullina, Raisa; Gafurov, Oleg; Malm, Tarja; Karjalainen, Tero; Gröhn, Olli; Giniatullin, Rashid
• Is Part Of: Neuropharmacology. Volume 149(2019)
• Page Start: 113
• Page End: 123
• Publication Date: 2019-05-01
• Subjects: Piezo receptors -- Yoda1 -- Trigeminal ganglion -- Migraine -- Pain; Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2019.02.015
• Languages: English
• ISSNs: 0028-3908

Abstract

Abstract: Background: Recent discovery of mechanosensitive Piezo receptors in trigeminal ganglia suggested the novel molecular candidate for generation of migraine pain. However, the contribution of Piezo channels in migraine pathology was not tested yet. Therefore, in this study, we explored a potential involvement of Piezo channels in peripheral trigeminal nociception implicated in generation of migraine pain. Methods: We used immunohistochemistry, calcium imaging, calcitonin gene related peptide (CGRP) release assay and electrophysiology in mouse and rat isolated trigeminal neurons and rat hemiskulls to study action of various stimulants of Piezo receptors on migraine-related peripheral nociception. Results: We found that essential (35%) fraction of isolated rat trigeminal neurons responded to chemical Piezo1 agonist Yoda1 and about a half of Yoda1 positive neurons responded to hypo-osmotic solution (HOS) and a quarter to mechanical stimulation by focused ultrasound (US). In ex vivo hemiskull preparation, Yoda1 and HOS largely activated persistent nociceptive firing in meningeal branches of trigeminal nerve. By using our novel cluster analysis of pain spikes, we demonstrated that 42% of fibers responded to Piezo1 agonist and 20% of trigeminal fibers were activated by Yoda1 and by capsaicin, suggesting expression of Piezo receptors in TRPV1 positive peptidergic nociceptive nerve fibers. Consistent with this, Yoda1 promoted the release of the key migraine mediator CGRP from hemiskull preparation. Conclusion: Taken together, our data suggest the involvement of mechanosensitive Piezo receptors, in particular, Piezo1 subtype in peripheral trigeminal nociception, which provides a new view on mechanotransduction in migraine pathology and suggests novel molecular targets for anti-migraine medicine. Highlights: Migraine originating from meninges is characterized by pulsating pain and mechanical allodynia. Piezo receptors expressed in meninges can be activated by mechanical or chemical stimuli such as Yoda1. Stimulation of Piezo receptors activates trigeminal neurons and triggers the release of CGRP. Cluster spike analysis revealed expression of Piezo1 receptors in nociceptive fibers of the trigeminal nerve. Piezo receptors can be involved in generation of migraine pain.