Migraine-relevant sex-dependent activation of mouse meningeal afferents by TRPM3 agonists

G Krivoshein,Amjm Van Den Maagdenberg,R A Giniatullin,E A Tolner

doi:10.1186/s10194-021-01383-8

Abstract

BackgroundMigraine is a common brain disorder that predominantly affects women. Migraine pain seems mediated by the activation of mechanosensitive channels in meningeal afferents. Given the role of transient receptor potential melastatin 3 (TRPM3) channels in mechanical activation, as well as hormonal regulation, these channels may play a role in the sex difference in migraine. Therefore, we investigated whether nociceptive firing induced by TRPM3 channel agonists in meningeal afferents was different between male and female mice. In addition, we assessed the relative contribution of mechanosensitive TRPM3 channels and that of mechanosensitive Piezo1 channels and transient receptor potential vanilloid 1 (TRPV1) channels to nociceptive firing relevant to migraine in both sexes.MethodsTen- to 13-week-old male and female wildtype (WT) C57BL/6 J mice were used. Nociceptive spikes were recorded directly from nerve terminals in the meninges in the hemiskull preparations.ResultsSelective agonists of TRPM3 channels profoundly activated peripheral trigeminal nerve fibres in mouse meninges. A sex difference was observed for nociceptive firing induced by either PregS or CIM0216, both agonists of TRPM3 channels, with the induced firing being particularly prominent for female mice. Application of Yoda1, an agonist of Piezo1 channels, or capsaicin activating TRPV1 channels, although also leading to increased nociceptive firing of meningeal fibres, did not reveal a sex difference. Cluster analyses of spike activities indicated a massive and long-lasting activation of TRPM3 channels with preferential induction of large-amplitude spikes in female mice. Additional spectral analysis revealed a dominant contribution of spiking activity in the α- and β-ranges following TRPM3 agonists in female mice.ConclusionsTogether, we revealed a specific mechanosensitive profile of nociceptive firing in females and suggest TRPM3 channels as a potential novel candidate for the generation of migraine pain, with particular relevance to females.

Highlights

Migraine is a common multifactorial brain disorder with a prevalence of approximately 15% [1, 2]
We propose that mechanosensitive ‘transient receptor potential melastatin 3’ (TRPM3) channels, which were recently shown to be expressed in human sensory neurons [14], are involved in the generation of migraine pain
Of relevance to migraine pathophysiology, TRPM3 channels co-localize in TG neurons with the nociceptive fibre neuropeptide calcitonin gene-related peptide (CGRP) [16], of which plasma levels were shown to be elevated during migraine headache [17] and antagonism of CGRP has proven effective in treating migraine [18]

Summary

Introduction

Migraine is a common multifactorial brain disorder with a prevalence of approximately 15% [1, 2]. We propose that mechanosensitive ‘transient receptor potential melastatin 3’ (TRPM3) channels, which were recently shown to be expressed in human sensory neurons [14], are involved in the generation of migraine pain. Their functional role in nociception is apparent given that TRPM3 channels sense noxious heat and TRPM3 deficient mice show reduced inflammatory pain [15]. Given the role of transient receptor potential melastatin 3 (TRPM3) channels in mechanical activation, as well as hormonal regulation, these channels may play a role in the sex difference in migraine. We assessed the relative contribution of mechanosensitive TRPM3 channels and that of mechanosensitive Piezo channels and transient receptor potential vanilloid 1 (TRPV1) channels to nociceptive firing relevant to migraine in both sexes

Methods

Results

Conclusion