Somatosensory cortical progesterone receptor signaling regulates the episodic to chronic migraine transformation

Women during their reproductive years are more susceptible to migraines than men, largely due to the effects of female reproductive hormones. Progesterone receptor (PR) signaling influences episodic migraine susceptibility. Here, we investigated the role of PRs in regulating the transformation from episodic to chronic migraine. Adult female and male C57Bl6 mice, female conditional PR knockout (PRKO) and littermate wild-type (WT) mice, and female mice expressing a Cre recombinase under the progesterone receptor (Pgr) promoter were used. Migraine transformation was induced using five systemic alternate-day nitroglycerin (NTG) injections. Periorbital mechanical thresholds were assessed using von Frey monofilaments. AAV9-mediated transduction was used to express muscarinic acetylcholine receptor-based DREADD complex hM4Di for silencing the activity of PR-expressing somatosensory cortical neurons. Somatosensory cortical neuronal activation was assessed using cFos immunohistochemistry. Gonadally intact female mice were three times more susceptible to developing transformed migraines; they experienced faster pain sensitization after repeated NTG injections compared to males, and their recovery from pain was also slower. PR agonist segesterone promoted migraine transformation in females. In contrast, migraine transformation was slower in PRKO females than in WT females, and their recovery was quicker. PRs are expressed in the somatosensory cortex, and after five NTG injections, there was stronger cFos immunoreactivity in the somatosensory, insular, and cingulate cortices of female WT mice than in PRKO mice. When PR-expressing somatosensory cortical neurons were chemo-genetically silenced, the transition from acute to chronic migraine slowed. PR activation on the somatosensory cortex neurons contributes to the transformation of acute to chronic migraine.