GENETIC AND MICRO-ENVIRONMENTAL FACTORS REGULATE THE ROLE OF ATP AS TRANSMITTER OF PAIN IN A MIGRAINE MODEL

Migraine headache is severe, persistent for hours and even days, and poorly controlled in many patients. Our ultimate goal is to devise a way to block the origin of such painful signals at source, namely at the level of the trigeminal sensory neurons which, during an acute migraine attack, are excited by locally released chemical substances and become supersensitive to pain stimuli. While sensitization is a fundamental process to trigger and perpetuate migraine pain, its mechanisms are poorly understood and are the subject of the present proposal based on animal models in vitro and in vivo. Our current project built on our previous Telethon grant has enabled us to set up trigeminal ganglion cells in culture as a model to examine what membrane proteins are upregulated by chemicals triggering migraine pain. We have observed that a common target for sensitization is the neuronal ATP-sensitive P2X3 receptor and that glial cells contribute to regulate its activity via other ATP receptors. The present proposal will focus on the processes underlying receptor sensitization to identify distinct mechanisms associated with the early stage of migraine pain, its strengthening and maintenance. Since we have recently established a colony of transgenic mice expressing the human gene of familial migraine, we will have the opportunity to study if trigeminal neurons of such animals are already sensitized to painful stimuli and how. We hypothesize that P2X3 receptor sensitization is regulated by satellite glial cells that are typically wrapped around trigeminal neurons, and it involves a gain of protein function followed by an increased number of membrane proteins to perpetuate pain. Once neuronal and glial mechanisms are identified, we will study how to block them with pharmacological agents or molecular biology techniques by also testing an in vivo mouse model of trigeminal pain. The outcome of our work can be exploited to design novel analgesic treatments for headache.