INTRODUCTION 🧠
Perioperative neurocognitive disorder (PND) represents a significant clinical challenge, particularly in the elderly population, as it involves a decline in cognitive function after surgery. While postoperative pain is already recognized as a contributing factor to PND, the impact of preoperative inflammatory pain remains underexplored. This study aimed to investigate how pre-existing inflammatory conditions, induced via Complete Freund's Adjuvant (CFA), influence both postoperative pain and the cognitive decline typically associated with surgery. Using a well-established tibial fracture model in aged C57BL/6 mice, we monitored pain sensitivity and behavioral changes in the days surrounding the surgical intervention. Our goal was to provide insight into the underlying biological mechanisms connecting preoperative inflammation, pain sensitization, and cognitive deterioration, and to uncover potential targets for therapeutic intervention.
MODEL ESTABLISHMENT AND STUDY DESIGN 🧪
To understand the relationship between inflammatory pain and cognitive outcomes after surgery, a dual-model approach was employed in 14-month-old C57BL/6 mice. First, an inflammatory pain model was induced by intraplantar injection of CFA, creating a persistent localized inflammatory state. One week later, a PND model was established through a tibial fracture surgery under anesthesia. Key physiological indicators such as paw withdrawal threshold and body weight were tracked to assess pain and systemic health. By designing a timeline that allowed preoperative inflammation to develop prior to surgical insult, the model closely mimics clinical scenarios where patients present with pre-existing pain conditions before undergoing surgery. This setup enabled precise investigation into how prior inflammation might sensitize the nervous system to exacerbate postoperative complications.
EFFECTS ON POSTOPERATIVE PAIN AND COGNITIVE FUNCTION 🔬
Our findings clearly demonstrate that preoperative CFA injection worsened postoperative outcomes. Mice exposed to CFA prior to surgery exhibited significantly lowered paw withdrawal thresholds postoperatively, indicating heightened pain sensitivity. In parallel, behavioral tests revealed more severe cognitive deficits in these mice compared to those undergoing surgery alone. These observations support the hypothesis that pre-existing inflammatory pain primes the central nervous system, creating a hyper-responsive state that amplifies the impact of surgical trauma. This synergy between chronic inflammation and surgical insult appears to increase both pain perception and vulnerability to neurocognitive dysfunction, further emphasizing the need for early detection and management of inflammation before surgery.
NEUROINFLAMMATORY RESPONSE IN THE HIPPOCAMPUS 🧬
One of the major mechanistic insights from this study relates to the elevated neuroinflammatory response observed in the hippocampus of CFA-treated mice post-surgery. Immunofluorescence and protein analyses revealed that the combination of CFA and surgery led to increased activation of microglia and astrocytes—two glial cell types involved in neuroinflammation. Correspondingly, we observed elevated levels of pro-inflammatory cytokines including IL-1β, IL-6, and TNF-α. These inflammatory markers are known to impair synaptic plasticity and neuronal function, providing a plausible link between glial activation and cognitive deficits. The heightened glial response indicates that preoperative inflammation not only exacerbates local pain but also triggers central inflammatory pathways that impair cognition.
α7nAChR AND CAP DYSFUNCTION AS A MECHANISM 🧩
The cholinergic anti-inflammatory pathway (CAP), mediated by the alpha7 nicotinic acetylcholine receptor (α7nAChR), plays a critical role in modulating inflammation in the brain. In this study, surgery-induced reduction in α7nAChR expression was further worsened by preoperative CFA administration. This downregulation impairs the CAP, potentially removing a key brake on neuroinflammation. Without proper cholinergic regulation, microglia and astrocytes remain activated longer, contributing to prolonged inflammatory signaling and neuronal damage. The loss of α7nAChR function thus appears to be a pivotal mechanism through which preoperative pain exacerbates cognitive outcomes, making it a potential target for therapeutic modulation in the context of PND.
ROLE OF HMGB1 IN INFLAMMATORY CASCADE 🔥
Another significant molecular finding was the overexpression of High Mobility Group Box 1 (HMGB1) protein in the hippocampus following surgery, especially in mice pre-treated with CFA. HMGB1 is a well-known danger-associated molecular pattern (DAMP) molecule that can activate toll-like receptors and promote cytokine release, thereby amplifying neuroinflammation. Its elevated expression indicates a prolonged and more aggressive inflammatory response in the brain when surgery is preceded by peripheral inflammation. Together with α7nAChR dysfunction, HMGB1 upregulation forms part of a vicious cycle that sustains glial activation and impairs recovery. These insights provide compelling evidence that managing preoperative inflammation could significantly reduce HMGB1-mediated neurotoxicity in surgical patients.
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#Neuroinflammation #PostoperativePain #CognitiveDisorder #PND #PreoperativePain #α7nAChR #HMGB1 #MicrogliaActivation #Astrocytes #BehavioralNeuroscience #MouseModel #Neurodegeneration #SurgeryModel #InflammatoryPain #CFA #TibialFracture #AgingBrain #IL6 #TNFalpha #NeuroscienceResearch
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