Estrous Cycle Induces Peripheral Sensitization in Trigeminal Ganglion Neurons: An Animal Model of Menstrual Migraine.

BACKGROUND: Many women experience menstrual migraines that develop into recurrent migraine attacks during menstruation. In the human menstrual cycle, the estrogen level fluctuates according to changes in the follicular and luteal phases. The rat estrous cycle is used as an animal model to study the effects of estrogen fluctuation. OBJECTIVE: To investigate whether the estrous cycle is involved in migraine development by comparing the neuronal excitability of trigeminal ganglion (TG) neurons in each stage of the estrous cycle. MATERIAL AND METHOD: Female rats were divided into four experimental groups based on examinations of the cytologies of vaginal smears, and serum analyses of estrogen levels following each stage of the estrous cycle. The rats in each stage of the estrous cycle were anesthetized and their trigeminal ganglia were removed The collections of trigeminal ganglia were cultured for two to three hours, after which whole-cell patch clamp experiments were recorded to estimate the electrophysiological properties of the TG neurons. RESULTS: There were many vaginal epithelial cells and high estrogen levels in the proestrus and estrus stages of the estrous cycle. Electrophysiological studies revealed that the TG neurons in the proestrus and estrus stages exhibited significantly lower thresholds of stimulation, and significant increase in total spikes compared to the TG neurons that were collected in the diestrus stage. CONCLUSION: Our results revealed that high estrogen levels in the proestrus and estrus stages altered the thresholds, rheobases, and total spikes of the TG neurons. High estrogen levels in the estrous cycle induced an increase in neuronal excitability and the peripheral sensitization of TG neurons. These findings may provide an explanation for the correlation of estrogen fluctuations during the menstrual cycle with the pathogenesis of menstrual migraines.

The estrous cycle modulates voltage-gated ion channels in trigeminal ganglion neurons.

Migraines typically occur more frequently in women than men because of the effects of estrogen on both the frequency and severity of migraine attacks. Many women suffer from migraine attacks during menstruation, which are known as menstrual migraines. The pathophysiology of menstrual migraines can be explored by using the rat estrous cycle, which shows a cyclical fluctuation of estrogen level that resembles the menstrual cycle. The aim of this study was to investigate whether different stages of the estrous cycle are involved in migraine development by comparing the excitability of trigeminal ganglion (TG) neurons in four different stages of the estrous cycle by using action potential (AP) parameter assessments. The stages of the estrous cycle were identified by a vaginal smear and measuring the estrogen levels in collected blood. The proestrus and estrus stages had higher estrogen levels compared with the diestrus and metestrus stages. Whole-cell patch clamp recordings demonstrated that TG neurons in the proestrus and estrus stage had lower AP threshold, lower rheobase, higher AP height, shorter AP falling time and deeper afterhyperpolarization (AHP) depth. Hence, our results revealed that the high level of estrogen in the proestrus and estrus stage alters the AP properties of TG neurons. Estrogen may increase membrane excitability and the summation of cellular responses, which alters the AP properties. The alterations of the AP properties in the proestrus and estrus stage may relate to a modification of voltage-gated ion channels in TG neurons, which is a pathogenesis for menstrual migraine. No COI.