Crosstalk between sensory neurons and neuroinflammatory cells in trigeminal ganglia in relation to migraine pain

Migraine is a disabling disease that, despite recent pharmacological progress, leaves some patients poorly controlled and gradually lapsing into chronic migraine with the risk of brain damage. Migraine progression results from changes in nociceptive threshold and ensuing central sensitization, namely hypersensitivity to multiple sensory stimuli with plasticity modifications in pain processing networks. Since brain tissue has no pain sensitivity, changes in nociceptive threshold and peripheral sensitization of trigeminal ganglion sensory neurons, which are key elements for transducing sensory stimuli from pain-sensitive structures of the head to the brainstem, seem pivotal for headache onset and disease maintenance. Neuronal sensitization is a subtle process involving crosstalk between ganglion neurons and non neuronal cells, including satellite cells. Whether patients normalize their trigeminal ganglion function between attacks and what predisposes them to headache remain poorly explained probably because of the heterogeneity of migraineurs. Previous studies show that mutation of a single gene responsible for the alpha subunit of CaV2.1 calcium channels causes a genetic type of migraine, familial hemiplegic migraine1 (FHM1). This mutation confers channel gain-of-function, i.e. enhanced influx of calcium into neurons. Thanks to previous research projects funded by Telethon, our research network demonstrated hyperfunctional ATP-activated P2X3 receptorchannels in trigeminal neurons from a knock-in (KI) mouse model reproducing such a mutation. We also detected an over-activation of G-protein coupled nucleotide-sensitive P2Y receptors on KI satellite glial cells following exposure to pro-algogenic molecules, suggesting that the purinergic system might play a role in the development and maintenance of trigeminal sensitization in migraine. Thus, the main aim of the present project is to understand what occurs to pain transduction mechanisms of trigeminal sensory neurons in migraine, why they become hyperactive, and how we could stop them. Our project based on translational research that combines basic and clinical studies using KI mice and FHM1 samples, proposes to identify the nature and mechanisms (including chemical messengers, with a specific focus on the purinergic system) used by trigeminal ganglion neurons to crosstalk with satellite cells, and how this process might recruit neuroimmune cells to create a latent sensitization upon which acute attacks are facilitated. Ultimately, we wish to find out if certain biomarkers of FHM1 determine or support the KI ganglion phenotype of sensitization, and how we can reverse it.