Estrogen Decreases Inflammatory Responses by Dampening Glial Cell Activation.

摘要

Important sex differences in the development and perception of pain have been found by numerous epidemiological studies. This dimorphic response to pain is attributed to distinct endocrinological profiles in males and females. For example, in females, 17β-estradiol has been shown to diminish behavioral responses to nociception induced by inflammation in various pain models. However, estrogen's anti-hyperalgesic mechanism during the nervous system's inflammatory response is yet to be clearly defined. Glial cells, in particular microglia and astrocytes, have been shown to play an influential role in the establishment of pain states. The objective of this study is to determine if estrogen exerts its anti-hyperalgesic effects by reducing glial cell responses in the dorsal horn of the spinal cord and/or immune cell responses at the injury site, and how this in turn influences intracellular signaling pathways that regulate pro-inflammatory events. To this end, the Cg model of inflammatory pain was used with eight-week old ovariectomized Sprague-Dawley female rats that were subcutaneously implanted with a silastic capsule containing either 20% 17β-estradiol or cholesterol (vehicle), and at varying time periods, they received an injection of either carrageenan or saline (vehicle). Hindpaw withdrawal latencies in response to different heat stimuli (4.5 mV, 4.9 mV, and 5.3 mV) were measured using the Hargreaves Paw Thermal Stimulator. The rats were then sacrificed, spinal cords were dissected, and immunohistochemistry was performed on paws to observe CD68 macrophage activity and on spinal cord sections to observe glial cell responses and IL-1β cytokine activity. Additionally, glial activation was correlation with levels of intracellular markers using Western blot analyses. Results reveal significantly dampened behavioral responses coupled with reduced glial activation in animals that received the estradiol treatment compared to animals that received the vehicle treatment. Additionally, estradiol treatment significantly reduced CD68 macrophage activity and IL-1β cytokine activity colocalized with glial activation. Correlations with intracellular markers did not reveal significant relationships with glial activity, but both the MAPK/ERK and JAK/STAT pathways were implicated in the estradiol-mediated inflammatory response in behavioral correlations. Taken together, our results suggest that estradiol's anti-inflammatory effects are mediated through the reduction of glial cell activity and consequent down-regulation of inflammatory mediators at the injury site and in the central nervous system.