β-Endorphin contributes to psychological stress- associated hippocampal microglial alterations and cognitive impairment.

Psychological stress is a risk factor for cognitive impairment, yet the molecular mechanisms linking stress exposure to hippocampal dysfunction remain incompletely understood. β-Endorphin (β-EP), an endogenous opioid peptide, has been implicated in stress-related processes; however, its contribution to stress-associated cognitive impairment remains unclear. Using a chronic psychological stress model, we found that stressed rats exhibited anxiety- and depression-like behaviors, impaired learning and memory, reduced hippocampal neuronal plasticity, and altered microglial morphology and functional responses. These changes were accompanied by elevated β-EP levels in serum and hippocampal tissue and elevated hippocampal μ-opioid receptor (MOR) and δ-opioid receptor (DOR) expression. In vivo pharmacological studies showed that β-EP administration recapitulated several stress-associated alterations, whereas naloxone partially attenuated these alterations in stressed rats. Using BV2 cells as an exploratory model, β-EP exposure induced cellular alterations, including increased cell proliferation and phagocytic activity, and these changes were partially attenuated by naloxone and the selective MOR and DOR antagonists CTOP and NTI. Transcriptomic analysis and subsequent validation revealed increased NLRP3 inflammasome-related signaling in β-EP-treated BV2 cells, while pharmacological inhibition with the selective NLRP3 inhibitor MCC950 attenuated β-EP-associated cellular alterations. Collectively, these findings suggest that β-EP contributes to psychological stress-associated cognitive deficits in association with opioid receptor signaling and microglial alterations, and suggest NLRP3 inflammasome-related signaling as a potential pathway involved in β-EP-associated cellular responses.