Targeted Acid-Sensing Ion Channel Therapies for Migraine

Acid-sensing ion channels (ASICs) are a family of ion channels, consisting of four members; ASIC1 to 4. These channels are sensitive to changes in pH and are expressed throughout the central and peripheral nervous systems—including brain, spinal cord, and sensory ganglia. They have been implicated in a number of neurological conditions such as stroke and cerebral ischemia, traumatic brain injury, and epilepsy, and more recently in migraine. Their expression within areas of interest in the brain in migraine, such as the hypothalamus and PAG, their demonstrated involvement in preclinical models of meningeal afferent signaling, and their role in cortical spreading depression (the electrophysiological correlate of migraine aura), has enhanced research interest into these channels as potential therapeutic targets in migraine. Migraine is a disorder with a paucity of both acute and preventive therapies available, in which at best 50% of patients respond to available medications, and these medications often have intolerable side effects. There is therefore a great need for therapeutic development for this disabling condition. This review will summarize the understanding of the structure and CNS expression of ASICs, the mechanisms for their potential role in nociception, recent work in migraine, and areas for future research and drug development.