We hypothesize that persistent activation of the endogenous CCL2-CCR2 signaling results in long-lasting sensitization of dura afferent neurons, thereby contributing to the generation of headache and to migraine chronification. We propose to conduct preclinical study to thoroughly validate the peripheral CCL2 and CCR2 as molecular targets for novel chronic migraine therapeutics.
Our preliminary study indicates that, despite the ubiquitous expression of TRESK K+ channel in all primary afferent neurons, de novo loss of TRESK selectively increases the excitability of trigeminal nociceptors, thereby enhancing trigeminal pain but not body pain in mice. In this application we aim to understand the mechanisms through which TRESK channels differentially regulate the transmission of trigeminal and body pain. We propose to test the hypothesis that migraine triggers and frequent attacks increase migraine susceptibility and facilitate migraine chronification through reducing TRESK activity in dural afferent neurons.