Migraine attacks are characterised by strong headache with persistent duration that originates from long-lasting sensitisation of nerve terminals of trigeminal ganglion neurons that innervate meninges. Despite complex and multiple mechanisms remain poorly understood, current theories propose that endogenous substances, like Calcitonin gene related peptide (CGRP) and Nerve growth factor (NGF), released during a migraine attack from the trigeminal-vascular system sensitize trigeminal neurons to transmit nociceptive signals to the brainstem. Recently CGRP receptor antagonists have been proposed and they are currently under clinical trials on migraine patients. Recent studies indicate that acute, long-lasting sensitization of trigeminal nociceptive neurons occurs via distinct processes involving enhanced expression and function of ATP-gated P2X3 receptors known to play a role in chronic pain. We demonstrated that in trigeminal neurons, CGRP induces in a slowly-developing up-regulation of the ionic currents mediated by P2X3 receptors by enhancing receptor trafficking to the neuronal membrane and activating their gene transcription. Such up-regulated receptors acquire the ability to respond repeatedly to extracellular ATP, thus enabling long-lasting signalling of painful stimuli. In contrast, NGF induces rapid, reversible up-regulation of P2X3 receptor function via protein kinase C phosphorylation, an effect counteracted by in vivo NGF neutralisation. Furthermore studying the functional role of P2X3 phosphorylation, we demonstrated that these receptors are controlled by tyrosine kinase Csk, that operate a new direct important negative modulatory action on sensory neuron exitability. Using a genetic animal model of migraine pain, we are currently studying novel aspects of neuronal signalling transduction mechanisms in trigeminal neurons. The diverse intracellular elements used by CGRP and NGF show that sensitization of P2X3 receptor function depends from the complex integrated action of multiple cellular pathways. Our findings imply that combinatorial strategies to inhibit a chronic migraine pain attack might be most efficient approaches, and their efficacy might highly depend on the time of administration.