The main aim of the our research project is to understand what occurs to pain transduction mechanisms of trigeminal sensory neurons in migraine, why they become hyperactive, and how we may stop them. Our project proposes to identify the chemical processes (including soluble messengers, with a specific focus on the purinergic system) used by trigeminal ganglion neurons to crosstalk with satellite glial cells (SGCs), and how this process might recruit neuroimmune cells to create a latent neuronal sensitization though which acute attacks are facilitated. To this end, we have employed tissues from a genetic mouse model of migraine, the Cav2.1 R192Q mutant knock-in (KI) mice expressing a human mutation causing familial hemiplegic migraine type 1 (FHM1). Concerning the role of metabotropic purinergic receptors, our data show that application of bradykinin (BK) to primary mixed trigeminal cultures induces neuronal release of the pro-algogenic mediator calcitonin gene-related peptide (CGRP), which in turn potentiates the ADP-responsive P2Y1 and the UTP-sensitive P2Y2 receptor subtypes on surrounding SGCs (Ceruti et al., J Neurosci 31:3638-49, 2011). The increased activity of P2 receptors is not only due to increased receptor protein expression, but also, and especially for the P2Y1 subtype, to modulation of the receptor localization to membrane lipid rafts. In vivo studies on the possible pro- or anti-algogenic role of these receptor subtypes are currently in progress. Interestingly, the anti-migraine drug sumatriptan fully inhibits both CGRP release and glial P2Y-receptor potentiation. Moreover, exposure to BK leads to increased production of PGE2, an effect completely abolished by the COX-1 inhibitor acetylsalicylic acid. The latter also blocks neuronal CGRP release. Taken together, these results suggest a possible role for receptors activated by adenine and uracil nucleotides in the mechanism of action of currently employed anti-migraine drugs. Unlike wild type (WT) trigeminal cultures, R192Q KI trigeminal ganglion cultures show basal macrophage activation together with enhanced TNFalpha release and neuronal currents mediated by P2X3 receptors. LPS application stimulates TNFalpha mRNA and WT P2X3 neuronal currents with faster recovery from desensitization (Franceschini et al. Purinergic Signal. 2012 in press). Furthermore, co-culturing WT or KI ganglia with host macrophages strongly stimulate phagocytosis (Franceschini et al. BMC Neurosci 2012 in press). These data suggest a basal neuroinflammatory profile in KI ganglia that facilitates the release of endogenous mediators (including ATP) to activate P2X3 receptors and amplify nociceptive signaling by trigeminal sensory neurons. The complex molecular cross-talk occurring even in basal conditions in KI ganglia further strengthen the role of purinergic receptors in the onset and maintenance of migraine-associated pain.
|Titolo:||Studies of familial hemiplegic migraine transgenic mouse models and patients to investigate the crosstalk between sensory neurons and neuroinflammatory cells in trigeminal ganglia in relation to migraine pain|
CERUTI, STEFANIA MARIA (Primo)
|Data di pubblicazione:||2013|
|Settore Scientifico Disciplinare:||Settore BIO/14 - Farmacologia|
|Citazione:||Studies of familial hemiplegic migraine transgenic mouse models and patients to investigate the crosstalk between sensory neurons and neuroinflammatory cells in trigeminal ganglia in relation to migraine pain / S. Ceruti, E. Fabbretti, S. Vilotti, G. Magni, D. Merli, C. Verderio, M.P. Abbracchio, A. Nistri. ((Intervento presentato al 17. convegno Convention Scientifica Telethon tenutosi a Riva del Garda nel 2013.|
|Appare nelle tipologie:||14 - Intervento a convegno non pubblicato|