Estrogen and serotonin enhance stress-induced visceral hypersensitivity in female rats by up-regulating brain-derived neurotrophic factor in spinal cord

Background We previously reported that female offspring of dams subjected to chronic prenatal stress (CPS) develop enhanced visceral hypersensitivity (VHS) following exposure to chronic stress in adult life that is mediated by up-regulation of spinal cord BDNF. The aims of this study were to examine the roles of estrogen receptor alpha (ER alpha) and an increase in spinal serotonin signaling in promoting this enhanced VHS in female rats and up-regulation of spinal cord BDNF transcription. Methods Pregnant dams were exposed to chronic stress from E11 until delivery. At 8 weeks, a chronic adult stress (CAS) protocol was applied for nine days. Key Results Ovariectomy before CAS or treatment with letrozole before and during CAS significantly prevented the development of enhanced VHS in female CPS+CAS rats. Intrathecal application of ER alpha siRNA significantly reduced VHS, decreased lumbar-sacral spinal cord expression of both ER alpha and BDNF, and reversed pro-transcriptional epigenetic modifications at BDNF promoter lX. Cerebrospinal fluid serotonin levels and 5HT3A receptor expression in the LS spinal cord were both significantly increased in female CPS+CAS rats. During CAS, intrathecal infusion of alosetron significantly decreased VHS, reduced BDNF and ER alpha expression in the LS spinal cord, and attenuated RNA pol II and ER alpha binding to the BNDF core promoter IX. Conclusions & inferences Serotonin-mediated activation of 5HT3A receptors in the spinal cord drives the development of enhanced female-specific VHS in our two hit CPS+CAS through up-regulation of spinal cord ER alpha.

Automated summary

The study found that female offspring of dams subjected to chronic prenatal stress develop enhanced visceral hypersensitivity following exposure to chronic stress in adult life, which is mediated by up-regulation of spinal cord BDNF, estrogen receptor alpha, and an increase in spinal serotonin signaling.