Mechanism of itch threshold regulation by estrogen

Abstract

In the life cycle of women, itching (pruritus) is commonly and clinically known to occur during periods such as pregnancy and menopause. However, the underlying causes of variations in this itching were previously unknown. We hypothesized that female hormones are involved in modulating itch sensitivity and investigated the effects of main female hormones, 17β-estradiol and progesterone, on the itch threshold using female rats. We demonstrated that 17β-estradiol increased scratching behavior induced by one of the peripheral itch mediators, histamine, in skin, indicating an increase in itch sensitivity. On the other hand, progesterone did not show an increase in itch sensitivity. To further elucidate the mechanism by which 17β-estradiol regulates itch sensitivity, we focused on the gastrin-releasing peptide receptor (GRPR), an itch-specific mediator in the spinal cord. 17β-estradiol revealed an increase in the firing frequency and sustained activity of spinal GRPR-expressing neurons upon itch stimulation of the skin. Moreover, the increased scratching behavior induced by 17β-estradiol was suppressed by a GRPR inhibitor. Taken together, our findings suggest that 17β-estradiol modulates the expression and activity of spinal GRPR-expressing neurons, leading to changes in itch sensitivity.