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. 2025 Apr 3:18:545-553.
doi: 10.1016/j.ibneur.2025.03.010. eCollection 2025 Jun.

Preoperative inflammatory pain exacerbates postoperative pain and neurocognitive impairment

Hui Yuan  1   2 , Daofan Sun  1 , Bo Lu  1 , Bo Meng  1   2 , Rongjun Liu  1 , Ruichun Wang  1 , Xiuzhong Xing  1   2 , Yiqin Ji  3 , Qianyu Ming  1   2 , Qiusheng Wang  1   2 , Junping Chen  1
Affiliations

Preoperative inflammatory pain exacerbates postoperative pain and neurocognitive impairment

Hui Yuan et al. IBRO Neurosci Rep. .

Abstract

Aims: Many studies have shown that postoperative pain aggravates perioperative neurocognitive disorder (PND). In this study we aimed to clarify the effect of preoperative inflammatory pain on postoperative pain and cognitive function.

Methods: We established the inflammatory pain model by injected complete freund adjuvant (CFA) and the PND model by tibial fracture surgery in 14- month-old C57BL/6 mice. The paw withdrawal threshold and body weight of the mice were measured 7 days before surgery and 3 days after surgery. On the third postoperative day, mice were subjected to behavioral testing or sacrificed to collect brain tissue.

Results: The result shows that CFA exacerbated postoperative pain and cognitive dysfunction in mice, enhanced surgery-induced activation of microglia and astrocytes in the hippocampus, and increased surgery-induced the overexpression of IL-1β, IL-6, and TNF-α, as well as aggravated the decreased expression of α7nAChR and the overexpression of HMGB1 in the hippocampus induced by surgery.

Conclusion: Our study shows that preoperative inflammatory pain further aggravates postoperative pain and neurocognitive dysfunction in aged rats, and the mechanism may be related to neuroinflammation caused by α7nAChR-mediated CAP dysfunction and high release of HMGB1.

Keywords: HMGB1; Neuroinflammation; Pain; Perioperative neurocognitive disorder; α7nAChR.

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Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Fig. 1
Fig. 1
Schematic of the experimental process.
Fig. 2
Fig. 2
Effects of CFA and surgery on mechanical pain threshold and BW in mice. (A) The changing trend of PWT of mice in each group. (B) The changing trend of BW of mice in each group. Data are depicted as the mean ± standard error (n = 10). ∗P<0.05 CFA group versus CON group; #P<0.05 SUR group versus CON group; &P<0.05 CFA+SUR group versus CFA group; ^P<0.05 CFA+SUR group versus SUR group.
Fig. 3
Fig. 3
Effects of CFA and surgery on neurocognitive function in mice. (A) The average speed in OF test. (B) The time in the central area in OF test. (C) Representative images of movement track in OF test. (D) The freezing time of the contextual fear memory in FC test. (E) The freezing time of the cued fear memory in FC test. Data are depicted as the mean ± standard error (n = 8). ∗P<0.05; ∗∗P<0.01.
Fig. 4
Fig. 4
Effects of CFA and surgery on the activation of microglia and astrocytes in the CA3 regions of the hippocampus. (A) Representative confocal microscopy analysis of Iba-1-positive microglia in the hippocampus. Scale bar 50μm. (B) Representative confocal microscopy analysis of GFAP-positive astrocytes in the hippocampus. Scale bar 50μm. (C) Quantitative of the percentage of Iba1-positive microglia area. (D) Quantitative of the percentage of GFAP-positive astrocytes area. Data are depicted as the mean ± standard error (n = 6). ∗P<0.05; ∗∗P<0.01.
Fig. 5
Fig. 5
Effects of CFA and surgery on the neuroinflammation in the hippocampus. (A) Expression of IL-1β in the hippocampus. (B) Expression of IL-6 in the hippocampus. (C) Expression of TNF-α in the hippocampus. Data are depicted as the mean ± standard error (n = 8). ∗P<0.05; ∗∗P<0.01.
Fig. 6
Fig. 6
Effects of CFA and surgery on hippocampal α7nAChR and HMGB1 expression. (A) Immunoblot bands of α7nAChR and HMGB1 in the hippocampus of mice. (B) Quantitative analysis of gray value of α7nAChR immunoblotting. (C) Quantitative analysis of gray value of HMGB1 immunoblotting. Data are depicted as the mean ± standard error (n = 5). ∗P<0.05; ∗∗P<0.01.
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