Estrogen relieved chronic pain-triggered cognitive dysfunction via restraining excessive inhibition in PV interneurons related to neuroinflammation.

BACKGROUND: Clinical studies showed that chronic pain conditions affected patients' cognitive function, but the specific mechanism remained unclear. Animal experiments revealed that compared with female mice, male mice experiencing chronic pain were more prone to hippocampal neuroinflammation and cognitive dysfunction. Parvalbumin-positive (PV) interneurons exerted a critical function in modulating cognitive performance. On the basis of these observations, the present study investigated the effects and underlying mechanisms of estrogen against chronic pain-triggered cognitive dysfunction. METHODS: To establish the chronic pain model, 8 weeks old male and female C57BL/6J mice were subjected to Sciatic Nerve Injury (SNI), and animal behavioral tests were conducted to evaluate their hippocampus-dependent memory capacity. Mechanical withdrawal threshold was measured to reflect the pain threshold in mice. Meanwhile, immunofluorescence and western blot were employed to detect microglial activation and the expression levels of plasticity-related proteins. Additionally, estrogen was used to replenish estrogen in the brain, and an estrogen receptor inhibitor was applied to block the effect of estrogen. The excitability of PV interneurons was examined via patch-clamp recordings, and chemogenetic manipulation was applied to regulate the excitability of PV interneurons. RESULTS: The SNI model could induce hippocampal neuroinflammation and cognitive dysfunction in male mice, and estrogen supplementation could improve cognitive function. Administration of the estrogen receptor inhibitor to female mice with chronic pain could cause hippocampal neuroinflammation and cognitive impairment. The estrogen content in the hippocampus was negatively correlated with the number of microglia. Chemogenetically inhibiting the excitability of hippocampal PV interneurons rescued cognitive impairments in male mice that underwent SNI surgery. CONCLUSION: Estrogen alleviated chronic pain-induced cognitive dysfunction by suppressing the neuroinflammation-mediated increase in the excitability of PV interneurons.