Progesterone receptors and migraine chronification

University Of Virginia, Charlottesville VA

Investigators

Abstract

Migraines are typified by unilateral throbbing headaches and hypersensitivity to light, sound, and touch. Migraines disproportionately affect women than men, particularly during the reproductive years. Female reproductive hormones are proposed to regulate migraine pathophysiology. Frequent migraine episodes, medication overuse, and incomplete relief from headaches from migraine therapies increase the risk of episodic (EM) to chronic migraine (CM) transformation characterized by headaches occurring on 15 or more days a month or headaches occurring despite anti-migraine therapies. Progesterone activates progesterone receptors (PRs) and induces gene expression. PRs are widely expressed in the brain, including in the migraine pain matrix. PR agonist treatment increased susceptibility to EM in female mice; whereas, their deletion rendered a degree of protection. Based on these findings we propose to test the hypothesis that PRs play a critical role in regulating the transition from episodic to chronic migraine and that altering PR expression in relevant neuronal populations will affect this transformation. We will use mice lacking PR expression in the central and peripheral nervous system, activity reporter TRAP2 (targeted recombination in active neuronal population), and mice with a floxed first exon of Pgr (PRfl/fl) crossed with Fos- CreER mice for these studies. In the first aim, we will use alternate-day nitroglycerin (NTG) injections to induce experimental migraine transformation. We will measure periorbital mechanical threshold, open field activity, and light aversion to assess evoked and spontaneous pain. We will use PR agonist segesterone, antagonist RU-486, and PR deletion in the central and peripheral nervous system to modulate PR signaling. In the second aim, we will elucidate unbiased whole-brain maps of neuronal activity at a single-cell resolution during the migraine transformation using TRAP2 mice and passive tissue clearing. We will determine the neuronal populations consistently activated during EM and identify changes in neuronal activation during migraine transformation. Finally, we will ablate PR expression in the neurons activated during migraine and evaluate if this alters the migraine transformation. These studies will provide insights into the role of PRs in regulating network transformation during migraine chronification and also deepen our understanding of hormonal regulation of the default network alterations that accompany chronic pain conditions, which are more prevalent in women.