Effects and mechanisms of oliceridine fumarate on postoperative cognitive dysfunction in elderly rats through TLR4/NF-κB pathway

XIE Dong; GENG Xiaoying; ZHU Yushan; LI Zhengxiang; YUAN Hengjie

doi:10.6039/j.issn.1001-0408.2026.11.09

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Effects and mechanisms of oliceridine fumarate on postoperative cognitive dysfunction in elderly rats through TLR4/NF-κB pathway

更新时间：2026-06-10

- Effects and mechanisms of oliceridine fumarate on postoperative cognitive dysfunction in elderly rats through TLR4/NF-κB pathway
- ZHONGGUO YAOFANG Vol. 37, Issue 11, Pages: 1434-1439(2026)
- 作者机构：
  
  1.天津医科大学总医院药剂科，天津　300052
  2.天津二七二医院药剂科，天津　300020
  3.天津医科大学药学院，天津　300070
- 作者简介：
- 基金信息：
- DOI：10.6039/j.issn.1001-0408.2026.11.09
  CLC： R965;R285
- Received：29 January 2026，
  
  Revised：2026-05-24，
  
  Accepted：25 May 2026，
  
  Published：15 June 2026
- 稿件说明：
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谢栋,耿晓颖,朱屿珊,等.富马酸奥赛利定通过TLR4/NF-κB通路改善老年大鼠术后认知功能障碍的作用及机制 [J].中国药房,2026,37(11):1434-1439.

XIE Dong,GENG Xiaoying,ZHU Yushan,et al.Effects and mechanisms of oliceridine fumarate on postoperative cognitive dysfunction in elderly rats through TLR4/NF-κB pathway[J].ZHONGGUO YAOFANG,2026,37(11):1434-1439.
谢栋,耿晓颖,朱屿珊,等.富马酸奥赛利定通过TLR4/NF-κB通路改善老年大鼠术后认知功能障碍的作用及机制 [J].中国药房,2026,37(11):1434-1439. DOI： 10.6039/j.issn.1001-0408.2026.11.09.

XIE Dong,GENG Xiaoying,ZHU Yushan,et al.Effects and mechanisms of oliceridine fumarate on postoperative cognitive dysfunction in elderly rats through TLR4/NF-κB pathway[J].ZHONGGUO YAOFANG,2026,37(11):1434-1439. DOI： 10.6039/j.issn.1001-0408.2026.11.09.

摘要

目的

基于Toll样受体4（TLR4）/核因子-κB（NF-κB）通路探究富马酸奥赛利定（TRV130）改善老年大鼠术后认知功能障碍（POCD）的作用及机制。

方法

将大鼠随机分为对照组（生理盐水）、模型组（生理盐水）、TRV130组（2.8 mg/kg）、TLR4/NF-κB通路抑制剂（TAK-242）组（3 mg/kg）、

-抑制蛋白抑制剂（Barbadin）组（3 mg/kg）和传统阿片类药物（吗啡）组（2.8 mg/kg），每组15只。除

对照组外，其余各组均构建POCD模型。从术后第1天起，尾静脉注射给药/生理盐水，每天1次，连续3 d。末次给药后，观察海马组织病理损伤情况；检测大鼠认知功能，血清中炎症因子水平，海马神经元凋亡率，海马组织中离子钙结合适配器分子1（Iba-1）、胶质纤维酸性蛋白（GFAP）和TLR4/NF-κB通路相关mRNA及其蛋白表达。

结果

模型组大鼠海马CA1区神经元排列紊乱、稀疏，数量减少，核固缩碎裂伴炎症细胞浸润。与对照组比较，模型组大鼠逃避潜伏期，肿瘤坏死因子α、白细胞介素6（IL-6）、IL-1β水平，海马神经元凋亡率，海马组织中Iba-1、GFAP平均荧光强度和TLR4、NF-κB p65 mRNA表达水平及其蛋白表达/磷酸化水平均显著延长/升高（

＜0.05）；目标象限停留时间、穿越平台次数均显著缩短/减少（

＜0.05）。与模型组比较，TRV130组、TAK-242组、Barbadin组大鼠认知功能、病理学、炎症及凋亡相关指标均显著改善（

＜0.05）；TRV130组、TAK-242组大鼠TLR4、NF-κB p65 mRNA表达水平及其蛋白表达/磷酸化水平均显著降低（

＜0.05）。

结论

TRV130可能通过抑制TLR4/NF-κB通路，减轻术后中枢神经炎症反应，进而改善老年大鼠POCD。

Abstract

OBJECTIVE

To investigate the effects and mechanisms of oliceridine fumarate （TRV130） in improving postoperative cognitive dysfunction （POCD） in elderly rats based on the Toll-like receptor 4 （TLR4）/nuclear factor-κB （NF-κB） pathway.

METHODS

Rats were randomly divided into the control group （normal saline）， the model group （normal saline）， the TRV130 group （2.8 mg/kg）， the TLR4/NF-κB pathway inhibitor （TAK-242） group （3 mg/kg）， the

-arrestin inhibitor （Barbadin） group （3 mg/kg）， and the traditional opioid drug （morphine） group （2.8 mg/kg）， with 15 rats in each group. Except for the control group， POCD models were established in all other groups. From the first day after surgery， drugs/normal saline were administered via caudal vein injection once daily for 3 consecutive days. After the last administration， the pathological damage of hippocampal tissue was observed； the cognitive function， serum inflammatory factor levels， hippocampal neurons apoptosis rate， and the expression of ionized calcium-binding adapter molecule 1 （Iba-1）， glial fibrillary acidic protein （GFAP）， and TLR4/NF-κB pathway-related mRNA and protein in hippocampal tissue were detected.

RESULTS

the model group， the neurons in the CA1 region of the hippocampus were disordered and sparse， with decreased number， pyknotic and fragmented nuclei accompanied by inflammatory cell infiltration. Compared with the control group， the escape latency， serum levels of tumor necrosis factor α （TNF-α）， interleukin-6 （IL-6）， and IL-1β， hippocampal neurons apoptosis rate， average fluorescence intensities of Iba-1 and GFAP， mRNA expression levels of TLR4 and NF-κB p65， and their protein expression/phosphorylation levels in hippocampal tissue were significantly increased/elevated in the model group （

＜0.05）； the time spent in the target quadrant and the number of platform crossings were significantly shortened/decreased （

＜0.05）. Compared with the model group， the cognitive function， pathological， inflammatory， and apoptosis-related indicators were significantly improved in the TRV130 group， TAK-242 group， and Barbadin group （

＜0.05）； the mRNA expression levels of TLR4 and NF-κB p65 and their protein expression/phosphorylation levels were significantly decreased in the TRV130 group and TAK-242 group （

＜0.05）.

CONCLUSIONS

TRV130 may improve POCD in elderly rats by inhibiting the TLR4/NF-κB pathway and alleviating postoperative central nervous system inflammatory responses.

关键词

Keywords

references

AREFAYNE N R ， BERHE Y W ， VAN ZUNDERT A A . Incidence and factors related to prolonged postoperative cognitive decline （POCD） in elderly patients following surgery and anaesthesia：a systematic review [J ] . J Multidiscip Healthc ， 2023 ， 16 ： 3405 - 3413 .

RUHNAU J ， MÜLLER J ， NOWAK S ， et al . Exploring neuroinflammation and its role in postoperative cognitive dysfunction following spine surgery [J ] . Gerontology ， 2026 ， 72 （ 1 ）： 29 - 40 .

XIONG M M ， LIU Y ， LIANG Y S ， et al . Opioid-free versus opioid-sparing anesthesia for postoperative pain and early recovery after laparoscopic cholecystectomy：a randomized controlled trial [J ] . J Pain Res ， 2025 ， 18 ： 2137 - 2146 .

SWINGLER M ， DONADONI M ， UNTERWALD E M ， et al . Molecular and cellular basis of mu-opioid receptor signaling：mechanisms underlying tolerance and dependence development [J ] . Front Neurosci ， 2025 ， 19 ： 1597922 .

WEBSTER L ， GUDIN J . Review of opioid abuse-deterrent formulations：impact and barriers to access [J ] . J Pain Res ， 2024 ， 17 ： 1989 - 2000 .

BERGESE S D ， BRZEZINSKI M ， HAMMER G B ， et al . ATHENA：a phase 3，open-label study of the safety and effectiveness of oliceridine （TRV130），a G-protein selective agonist at the µ-opioid receptor，in patients with moderate to severe acute pain requiring parenteral opioid therapy [J ] . J Pain Res ， 2019 ， 12 ： 3113 - 3126 .

SHAH A ， SHAH R ， FAHIM G ， et al . A dive into oliceridine and its novel mechanism of action [J ] . Cureus ， 2021 ， 13 （ 10 ）： e19076 .

BEARD T L ， MICHALSKY C ， CANDIOTTI K A ， et al . Oliceridine is associated with reduced risk of vomiting and need for rescue antiemetics compared to morphine：explora- tory analysis from two phase 3 randomized placebo and active controlled trials [J ] . Pain Ther ， 2021 ， 10 （ 1 ）： 401 - 413 .

FENG A C ， THOMAS B J ， PURBEY P K ， et al . The transcription factor NF-κB orchestrates nucleosome remodeling during the primary response to Toll-like receptor 4 signaling [J ] . Immunity ， 2024 ， 57 （ 3 ）： 462 - 477.e9 .

ZHANG T ， LIANG W ， OU W ， et al . Daphnetin alleviates neuropathic pain in chronic constrictive injury rats via regulating the NF-κB dependent CXCL1/CXCR2 signaling pathway [J ] . Pharm Biol ， 2023 ， 61 （ 1 ）： 746 - 754 .

蒋瑞，张乃心，赵楠，等 . 衰老大鼠术后认知功能障碍模型构建以及金钗石斛对该模型大鼠治疗效果评价 [J ] . 西部医学， 2025 ， 37 （ 10 ）： 1438 - 1444，1450 .

唐林，刘慧敏，罗柳，等 . 微小RNA-34a调控CaMKⅡ/CREB途径改善异氟烷麻醉引起的老年大鼠认知功能障碍 [J ] . 实用临床医药杂志， 2024 ， 28 （ 19 ）： 41 - 47 .

SINGLETON S ， BAPTISTA-HON D T ， EDELSTEN E ， et al . TRV130 partial agonism and capacity to induce anti-nociceptive tolerance revealed through reducing available μ-opioid receptor number [J ] . Br J Pharmacol ， 2021 ， 178 （ 8 ）： 1855 - 1868 .

刘紫阳，杨凯，邓婷，等 . TAK242阻断TLR4通路起到对脓毒性心肌损伤和心功能障碍的保护作用 [J ] . 中华危重病急救医学， 2021 ， 33 （ 10 ）： 1226 - 1231 .

HE Y ， LIU H ， YIN N ， et al . Barbadin potentiates long-term effects of lorcaserin on POMC neurons and weight loss [J ] . J Neurosci ， 2021 ， 41 （ 26 ）： 5734 - 5746 .

WANG T ， SUN G W ， TAO B D . Updated insights into the NLRP3 inflammasome in postoperative cognitive dysfunction：emerging mechanisms and treatments [J ] . Front Aging Neurosci ， 2024 ， 16 ： 1480502 .

SAFAVYNIA S A ， GOLDSTEIN P A . The role of neuroinflammation in postoperative cognitive dysfunction：moving from hypothesis to treatment [J ] . Front Psychiatry ， 2019 ， 9 ： 752 .

NURCAHYO W I ， HADISAPUTRO S ， MUTTAQIN Z ， et al . Difference in GFAP levels in POCD and non-POCD patients after on pump CABG [J ] . Vasc Health Risk Manag ， 2022 ， 18 ： 915 - 925 .

SUN Z Z ， NYANZU M ， YANG S ， et al . VX765 attenuates pyroptosis and HMGB1/TLR4/NF-κB pathways to improve functional outcomes in TBI mice [J ] . Oxid Med Cell Longev ， 2020 ， 2020 ： 7879629 .

王玲，杜潇，祝华莲，等 . 槲皮素调控TLR4/NF-κB通路对阿尔茨海默病大鼠认知功能障碍及海马神经元损伤的影响 [J ] . 中医药导报， 2023 ， 29 （ 12 ）： 19 - 23，52 .

郑丽丽，刘美岑 . 醒脑静基于TLR4/NF-κB信号通路改善热射病大鼠神经炎症与认知功能障碍 [J ] . 神经药理学报， 2024 ， 14 （ 2 ）： 1 - 6 .

BULL F A ， BAPTISTA-HON D T ， LAMBERT J J ， et al . Morphine activation of mu opioid receptors causes disinhibition of neurons in the ventral tegmental area mediated by β-arrestin2 and c-Src [J ] . Sci Rep ， 2017 ， 7 （ 1 ）： 9969 .

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