Cognitive and Affective Dysregulation in Neuropathic Pain: Associated Hippocampal Remodeling and Microglial Activation

Neuropathic pain is a persistent and exhausting condition which results from damage to the nervous system and is often accompanied by emotional and cognitive impairments. In this study, we investigated dynamic changes in pain-related behaviors over 8 weeks using a spared nerve injury (SNI) model in male C57Bl/6 mice. We examined behavioral outcomes in conjunction with glial activation, neurogenesis, and glutamatergic signaling in the hippocampus to elucidate the mechanisms underlying cognitive and affective alterations associated with chronic pain. Our findings demonstrate that SNI-induced neuropathic pain progressively increases anxiety-like behavior and impairs both working and long-term memory. These behavioral deficits are accompanied by significant activation of microglia and astrocytes, a reduction in hippocampal neurogenesis, and a decrease in the expression of NMDA and AMPA glutamate receptor subunits and the scaffolding protein PSD-95. Taken together, our results suggest that hippocampal neuroinflammation and associated synaptic dysfunction contribute to the affective and cognitive disturbances observed in chronic pain, providing insight into potential molecular targets for therapeutic intervention.