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Updated: Jun 2, 2025
A Mouse Model of Orthopedic Surgery to Study Postoperative Cognitive Dysfunction and Tissue Regeneration
Published on: February 27, 2018
Postoperative analgesia with morphine promoting microglial activation and neuroinflammation induced by surgery
Xiuzhi Shao1, Liping Xie1, Jingwen Zhai1
1Department of Anesthesiology, The First Affiliated Hospital of Shihezi University, Shihezi 832002, China.
Introduction:
Perioperative neurocognitive dysfunction (PND) is a significant challenge for patients who need surgery worldwide. Morphine can trigger an intense inflammatory reaction in the central nervous system (CNS) at the same time as analgesia, thus adverse effects aggravating PND. Microglia polarization is closely involved in the regulation of neuroinflammation and the TLR4/MyD88/NF-κB signaling pathway. However, the mechanisms of morphine analgesia aggravating PND impairment remain unclear.
Methods:
Tibial fracture surgery was performed in 18 months old male C57BL/6 J mice to mimic human orthopedic surgery and postoperative analgesia with morphine hypodermic or ropivacaine. Levels of inflammatory factors in the hippocampus, activation, and phenotype of microglia, an essential protein of TLR4/MyD88/NF-κB signal pathway, synaptic plasticity, and hippocampal-dependent memory function were evaluated after surgery and postoperative analgesia.
Results:
Morphine postoperative analgesia increased the expression of pro-inflammatory cytokines IL-1 β, IL-6, and TNF-α, decreased the level of anti-inflammatory IL-10, aggravated the activation of microglia and the destruction of synaptic plasticity in the hippocampus, resulting in hippocampal neuron loss, a significant decrease in the number of synapses and cognitive impairment in aged mice. In addition, the aggravation of neuroinflammatory response and the activation of microglia may be mediated by TLR4/MyD88/NF- κ B signal pathway.
Conclusion:
Our results demonstrate that morphine postoperative analgesia may aggravate microglia activation and neuroinflammation in the hippocampus by regulating the TLR4/MyD88/NF- κ B signal pathway and inhibiting the synaptic plasticity hippocampal neurons. It aggravated the acute cognitive decline and cognitive impairment after tibial fracture in elderly mice.
Insights
Morphine analgesia after surgery worsens cognitive decline in elderly mice by increasing neuroinflammation and damaging brain cell connections. This occurs via the TLR4/MyD88/NF-κB pathway, impacting memory and synaptic plasticity.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Perioperative neurocognitive dysfunction (PND) is a major surgical complication.
- Morphine, while providing pain relief, can exacerbate PND by causing central nervous system inflammation.
- Microglia activation and the TLR4/MyD88/NF-κB pathway are implicated in neuroinflammation.
Purpose of the Study:
- To investigate the mechanisms by which morphine analgesia aggravates PND.
- To explore the role of microglia polarization and the TLR4/MyD88/NF-κB pathway in morphine-induced PND.
Main Methods:
- Tibial fracture surgery and postoperative analgesia with morphine or ropivacaine in aged mice.
- Assessment of inflammatory factors, microglia activation, TLR4/MyD88/NF-κB pathway proteins, synaptic plasticity, and memory function in the hippocampus.
Main Results:
- Morphine increased pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) and decreased IL-10.
- Morphine aggravated microglia activation, synaptic plasticity damage, and cognitive impairment.
- Neuroinflammation and microglia activation were linked to the TLR4/MyD88/NF-κB pathway.
Conclusions:
- Morphine analgesia exacerbates PND by promoting microglia activation and neuroinflammation.
- The TLR4/MyD88/NF-κB pathway mediates morphine's negative effects on synaptic plasticity and cognitive function.
- These findings highlight potential therapeutic targets for mitigating PND.
