During chronic pain conditions, a cross-communication between sensory neurons and satellite glial cells (SGCs) within the trigeminal ganglia (TG), contributes to the development of hyperalgesia and allodynia. Since the purinergic system plays a special role in neuron-to-glia signalling, our purpose is to study in vitro and in vivo the involvement of G protein-coupled P2Y receptors in TG pain transmission. By using primary mixed TG cultures we previously showed that the proinflammatory mediator bradykinin (BK) potentiated purinergic P2Y receptors expressed by SGCs. Since BK receptors were functional in neurons only and BK was ineffective on neuron-free SGCs cultures, we hypothesized that the neuronal release of a soluble molecule was responsible of BK effects on SGCs. We identified this molecule as the calcitonin gene related peptide (CGRP), since its levels were markedly increased by BK application, and the CGRP antagonist, CGRP8-37, inhibited BK-induced effects on P2Y receptors. Interestingly, we found an increased CGRP release in cultures from a genetic mouse model of familial hemiplegic migraine, suggesting that the cross-talk with the purinergic system could be even more important in pathological conditions. To delve into the role of specific P2Y receptor subtypes in pain transmission, we set up a chronic inflammatory model in rat based on the injection of the complete Freund adjuvant (CFA) into the temporo mandibular joint (TMJ). The development of inflammation was confirmed by Evans blue dye extravasation in the ipsilateral TMJ, and by the increased orofacial pain sensitivity. Immunohistochemistry showed a significant GFAP upregulation on SGCs in the ipsilateral TG after CFA injection, as well as microglial activation in the ipsilateral medulla oblongata. We are now planning to selectively target specific P2Y receptors in vivo to evaluate their pro- or anti-algogenic role for the development of innovative analgesic drugs.
Role of P2Y purinergic receptors in neuron-glia signaling in trigeminal ganglia: involvement in pain transmission / G. Villa, S.M. Ceruti, M. Fumagalli, L. Colombo, M. Zanardelli, C. Verderio, A.M. van den Maagdenberg, A. Bhargava, L. Jasmin, P.T. Ohara, M.P. Abbracchio. ((Intervento presentato al convegno Next Step: la giovane ricerca avanza tenutosi a Milano nel 2010.
Role of P2Y purinergic receptors in neuron-glia signaling in trigeminal ganglia: involvement in pain transmission
G. Villa;S.M. Ceruti;M. Fumagalli;L. Colombo;M.P. Abbracchio
2010
Abstract
During chronic pain conditions, a cross-communication between sensory neurons and satellite glial cells (SGCs) within the trigeminal ganglia (TG), contributes to the development of hyperalgesia and allodynia. Since the purinergic system plays a special role in neuron-to-glia signalling, our purpose is to study in vitro and in vivo the involvement of G protein-coupled P2Y receptors in TG pain transmission. By using primary mixed TG cultures we previously showed that the proinflammatory mediator bradykinin (BK) potentiated purinergic P2Y receptors expressed by SGCs. Since BK receptors were functional in neurons only and BK was ineffective on neuron-free SGCs cultures, we hypothesized that the neuronal release of a soluble molecule was responsible of BK effects on SGCs. We identified this molecule as the calcitonin gene related peptide (CGRP), since its levels were markedly increased by BK application, and the CGRP antagonist, CGRP8-37, inhibited BK-induced effects on P2Y receptors. Interestingly, we found an increased CGRP release in cultures from a genetic mouse model of familial hemiplegic migraine, suggesting that the cross-talk with the purinergic system could be even more important in pathological conditions. To delve into the role of specific P2Y receptor subtypes in pain transmission, we set up a chronic inflammatory model in rat based on the injection of the complete Freund adjuvant (CFA) into the temporo mandibular joint (TMJ). The development of inflammation was confirmed by Evans blue dye extravasation in the ipsilateral TMJ, and by the increased orofacial pain sensitivity. Immunohistochemistry showed a significant GFAP upregulation on SGCs in the ipsilateral TG after CFA injection, as well as microglial activation in the ipsilateral medulla oblongata. We are now planning to selectively target specific P2Y receptors in vivo to evaluate their pro- or anti-algogenic role for the development of innovative analgesic drugs.
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