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

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 alpha- and beta-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.Functional Genomics of Muscle, Nerve and Brain Disorder

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

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 alpha- and beta-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.Functional Genomics of Muscle, Nerve and Brain Disorder

Migraine-relevant sex-dependent activation of mouse meningeal afferents by TRPM3 agonists (vol 23, 4, 2022)

Paroxysmal Cerebral Disorder

Mast Cell Mediators as Pain Triggers in Migraine: Comparison of Histamine and Serotonin in the Activation of Primary Afferents in the Meninges in Rats

© 2020, Springer Science+Business Media, LLC, part of Springer Nature. The meninges around the brain are characterized by an abundant blood supply, a high density of sensory nerves, and large numbers of mast cells. In migraine, the commonest neurological disorder, activation of trigeminal nerve fibers in the meninges is the initial trigger mechanism for generating pain signals. The recently suggested concept of the neuroimmune synapse suggests that mast cell transmitters can activate receptor proteins in close-lying nerve endings, leading to the generation of nociceptive spike activity. Serotonin and histamine, presumptive triggers for migraine, are classical transmitters released on activation of mast cells. Our recent research has identifi ed powerful activation of primary afferents by serotonin, mediated mainly via 5-HT3 receptors. However, the role of histamine in meningeal neuroimmune synapses has received little study. The present study therefore used recording of spike activity from primary afferents in the meninges in rats to study the role of histamine as a possible trigger for pain in migraine. Results from testing a wide range of histamine concentrations identified only a minimal (about 12%) effect with 10 μM histamine on the nociceptive activity of the trigeminal nerve. More detailed cluster analysis showed that the proportion of fibers reacting to histamine was no more than 29%, increases in spike activity in these fibers being significantly lower than on exposure to serotonin. Longer (4 h) exposure to histamine also produces no significant change in trigeminal nerve activity. The results do not exclude a stimulatory role for histamine in migraine but suggest that this mast cell transmitter has an action other than activation of the trigeminal nerve