Linking Pain and Delirium via Microglial Activation: A Mouse Study Using BSEEG, Behavioral Assays, Immunohistochemistry, and RNA Sequencing
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Background
The rising incidence of delirium in surgical and critical care settings, especially in older patients, calls for improved preventative and management strategies. Chronic pain is increasingly recognized as a key risk factor for delirium, and microglial activation may be the central mediator linking these two conditions.
Methods
We used a spared nerve injury (SNI) model of persistent neuropathic pain in tandem with a postoperative delirium (POD) mouse model. Pain assessments, electroencephalography (EEG) recording, and immunofluorescence were performed to characterize pain and delirium-like states. Microglia were isolated for RNA-seq to elucidate gene expression changes comprehensively.
Results
SNI mice showed persistent mechanical hypersensitivity from Day 7 onwards and demonstrated disrupted sleep-wake patterns in EEG indices. Immunofluorescence revealed sustained microglial activation in both the hippocampus and cortex following SNI. RNA-seq analyses indicated the upregulation of pro-inflammatory pathways (e.g., interleukin-6 production, NF-κB signaling) in SNI mice that also underwent head-mount surgery. Notably, the coincidence of persistent pain and an acute delirium-like state further exacerbated neuroinflammation.
Conclusion
Our findings suggest that neuropathic pain-induced microglial activation primes the brain for exaggerated inflammatory responses under additional surgical stress, potentially worsening delirium. Further investigations into microglia-focused therapies may inform novel strategies for mitigating delirium in patients with neuropathic pain.
