It is now known that glial cells directly participate to the genesis and maintenance of chronic pain, both in the central and in the peripheral nervous system, through their functional cross-talk with pain-transducing neurons [1]. The whole molecular network at the basis of this neuron-to-glia communication is still largely unknown, and the purinergic system is likely to play a key role in close conjunction with other pain-transducing systems [2, 3]. Therefore, we decided to study the contribution of the G protein-coupled P2Y purinergic receptors in pain transmission in the spinal-trigeminal system both in vitro and in vivo. In primary mixed trigeminal cultures, we showed that the pro-algogenic molecule bradykinin potentiates P2Y receptors expressed by satellite glial cells (SGCs) [4] through the neuronal release of calcitonin gene related peptide (CGRP), which in turn activates the ERK1/2 pathways in SGCs [5]. Interestingly, in cultures from a genetic mouse model of familial hemiplegic migraine we observed an increased CGRP release and an up-regulation in the number of SGCs showing functional P2Y receptors, suggesting that the role of the purinergic system in neuron-glia crosstalk is even more important under pathological conditions [5].
To study the pro- or anti-algogenic role of specific P2Y receptor subtypes in vivo, we next set up a sub-chronic inflammatory model in vivo by injecting complete Freund adjuvant (CFA) into the temporomandibular joint (TMJ). CFA-injected animals showed mechanical allodynia and TMJ edema, accompanied by a strong increase in the number of reactive SGCs and resident macrophages in the TG, and by microglial activation in the ipsilateral medulla oblongata [6]. We are now evaluating the pro- or anti-algogenic role of specific P2Y-receptor subtypes in pain transduction.
Overall, our results suggest that P2Y receptors on glial cells might represent innovative targets for the development of effective analgesic drugs.
References
[1] M. Takeda, M. Takahashi, S. Matsumoto. Contribution of the activation of satellite glia in sensory ganglia to pathological pain. Neuroscience Biobehavioural Reviews, 33, 784-792, 2009.
[2] D. Donnelly-Roberts, S. McGaraughty, C.C. Shieh, P. Honore, M.F. Jarvis. Painful purinergic receptors. Journal of Pharmacology and Experimental Therapeutics, 324, 409-415, 2009.
[3] G. Villa, M. Fumagalli, C. Verderio, M.P. Abbracchio, S. Ceruti. Expression and contribution of satellite glial cells purinoceptors to pain transmission in sensory ganglia: an update. Neuron Glia Biol, 6, 31-42, 2010.
[4] S. Ceruti, M. Fumagalli, G. Villa, C. Verderio, M.P. Abbracchio. Purinoceptor-mediated calcium signaling in primary neuron-glia trigeminal cultures. Cell Calcium, 43, 576-90, 2008.
[5] S. Ceruti, G. Villa, M. Fumagalli, L. Colombo, G. Magni, M. Zanardelli, E. Fabbretti, C. Verderio, A.M. van den Maagdenberg, A. Nistri, M.P. Abbracchio. Calcitonin Gene-Related Peptide-Mediated Enhancement of Purinergic Neuron/Glia Communication by the Algogenic Factor Bradykinin in Mouse Trigeminal Ganglia from Wild-Type and R192Q Cav2.1 Knock-In Mice: Implications for Basic Mechanisms of Migraine Pain. J Neurosci, 31, 3638-3649, 2011.
[6] G. Villa, S. Ceruti, M. Zanardelli, G. Magni, L. Jasmin, P.T. Ohara, M.P. Abbracchio. Temporomandibular join inflammation activates glial and immune cells in both the trigeminal ganglia and the spinal trigeminal nucleus. Mol Pain, 6, 89, 2010