P2Y purinergic receptors in neuron-to-glia communication in trigeminal ganglia and their role in migraine pain

Trigeminal satellite glial cells (SGCs) express G protein-coupled P2Y receptors for extracellular nucleotides (ATP, ADP, and UTP), whose activity is increased by exposure to bradykinin (BK) in vitro. However, their possible role in the development and maintenance of migraine pain is still unknown. Here we show the existence of a cross-communication between neurons and SGCs leading to glial P2Y receptor upregulation. In fact, BK induced the neuronal release of CGRP, which in turn activated an ERK1/2-dependent pathway in surrounding SGCs and potentiated P2Y receptors. Indeed, BK-mediated effects were inhibited by the anti-migraine drug sumatriptan, which targets neurons. Interestingly, both basal and BK-stimulated CGRP release was higher in trigeminal cultures from CaV2.1 α1 R192Q mutant knock-in (KI) mice, a model of familial hemiplegic migraine type 1. Indeed, BK significantly up-regulated the number of SGCs with functional P2Y receptors in cultures from KI mice only, suggesting that this cross-talk might become even more important in migraine-prone conditions, and that P2Y receptors might represent innovative targets for the development of therapeutic agents against migraine pain.