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Migraine headache is the most common neurological disorder and one of the most common chronic pain conditions. Approximately 18% of women and 6% of men in the US suffer from migraine with many patients suffering from multiple attacks per month (data courtesy of the Migraine Research Foundation). During an attack, patients at the very least are unable to perform some of their typical activities and at worst the attacks can be completely debilitating. Although there are drugs used to treat migraine (e.g. triptans, NSAIDs, prophylactic agents such as beta-blockers and antiepileptics), these drugs show efficacy in less than 50% of patients leaving a substantial number of migraineurs untreated. Discovery of new drugs has been limited, in part, by a lack of appropriate therapeutic targets. Research in the Dussor laboratory is aimed at understanding the pathophysiology that contributes to migraine and other forms of headache in order to uncover new therapeutic targets for headache treatment.
Although there is no sensory innervation of the brain itself, and thus stimulation of the brain is not painful, it has been known for over 70 years that stimulation of the meninges covering the brain does produce pain. Despite these many decades of research, the mechanisms by which pain signaling from the meninges occurs are still poorly understood. We have taken a multi-angled approach to investigate this problem. First, sensory neurons that innervate the meninges are isolated via application of a retrograde tracer to the dura. Once the tracer has been transported back to the trigeminal ganglion, neurons are cultured and retrogradely-labeled cells (i.e. dural-projecting neurons) are studied using in vitro patch-clamp electrophysiology. Our focus is on ion channels expressed on this population of neurons as these channels likely contribute to activation and/or sensitization of signaling from the meninges. We have recently found that dural afferents are extremely sensitive to even small changes in extracellular pH via the activation of acid-sensing ion channels (ASICs), suggesting both a role for these channels in headache and blockers of ASICs as novel headache treatments.
We also utilize preclinical in vivo headache models in which the dura is stimulated directly and behaviors consistent with headache are measured. These behaviors are changes in exploratory activity, which is consistent with a decreased desire to perform normal functions in humans, and cutaneous allodynia, which is a hypersensitivity of the skin that many migraine patients experience during the headache phase. Using these models, we have found that stimulating the meninges with decreased pH (again via activation of ASICs) produces behavioral responses consistent with headache, additionally supporting a role for ASICs in headache pathology. We are continuing to explore how ASICs contribute to pain signaling from the meninges and how this type of signaling might change under conditions that are believed to be present before and during migraine.
The laboratory is also performing research investigating other mechanisms of activation and sensitization of dural afferents in order to further uncover the potential pathophysiology that leads to migraine headache. Our ultimate goal is to generate potential targets for new migraine therapeutics in order to provide relief for the many patients who are not being adequately treated by currently available drugs.