ROLE OF ATP AS TRANSMITTER OF PAIN IN MIGRAINE

Migraine is a common disease with strong genetic component, characterized by recurrent attacks incapacitating patients through a combination of neurological symptoms and intense headache lasting for 1-3 days. Although migraine can be prevented with drugs and changes in patient lifestyle, prevention is often ineffective and justifies the search for effective and well tolerated new drugs. Our project intends to identify the basic mechanisms responsible for migraine pain with the ultimate aim of developing new drugs. For this purpose we shall study how trigeminal ganglion neurons, which are responsible for generating migraine pain, can become more responsive to painful signals normally caused by the pain transmitter ATP binding to distinct membrane proteins (“receptors”) on the surface of such cells. We intend to study the possibility that certain substances released by brain cells prior to migraine headache can perturb the normal operation of ATP receptors allowing persistent pain signalling. For this purpose we shall use simple in vitro models of trigeminal neurons in culture to investigate if there is a dysfunction in the operation of their ATP receptors. We will mimic migraine-like conditions by administering substances known to be released just prior to the manifestation of migraine headache. We will then investigate how ATP receptors can be altered with particular attention being paid to the molecular processes which enable such receptors to remain operational for a long time like during headache. Moreover, using trigeminal neurons from genetically modified mice which express the mutated gene responsible for a hereditary form of migraine, we will study how the function of their ATP receptors compares with that of normal mice. We believe that our work will be useful to elucidate important migraine pathways that can be exploited to design novel analgesics to treat headache and to establish an assay to test new therapeutic approaches to migraine pain