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The Journal of Headache and Pain

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Open Access 01-12-2022 | Migraine | Research article

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

Authors: G. Krivoshein, E. A. Tolner, AMJM van den Maagdenberg, R. A. Giniatullin

Published in: The Journal of Headache and Pain | Issue 1/2022

Abstract

Background

Migraine 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.

Methods

Ten- 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.

Results

Selective 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.

Conclusions

Together, 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.

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Title: Migraine-relevant sex-dependent activation of mouse meningeal afferents by TRPM3 agonists
Authors: G. Krivoshein
E. A. Tolner
AMJM van den Maagdenberg
R. A. Giniatullin
Publication date: 01-12-2022
Publisher: Springer Milan
Keywords: Migraine
Capsaicin
Published in: The Journal of Headache and Pain / Issue 1/2022
Print ISSN: 1129-2369
Electronic ISSN: 1129-2377
DOI: https://doi.org/10.1186/s10194-021-01383-8

Keynote webinar | Spotlight on medication adherence

Springer Medicine

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

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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