慢性不可预知性应激与完全弗氏佐剂、福尔马林诱导的妊娠期疼痛-抑郁共病小鼠模型的构建与评价

doi:10.12300/j.issn.1674-5817.2024.005

实验动物与比较医学 ›› 2024, Vol. 44 ›› Issue (3): 259-269.DOI: 10.12300/j.issn.1674-5817.2024.005

慢性不可预知性应激与完全弗氏佐剂、福尔马林诱导的妊娠期疼痛-抑郁共病小鼠模型的构建与评价

张一粟¹^,²(), 刘欣茹¹^,², 武若杰¹^,², 刘睿¹^,², 欧阳红², 李晓红¹()()

^1.蚌埠医科大学第一附属医院麻醉科, 蚌埠 233000
^2.蚌埠医科大学研究生院, 蚌埠 233000

收稿日期:2024-01-10 修回日期:2024-05-09 出版日期:2024-06-25 发布日期:2024-06-25
通讯作者: 李晓红（1966—），女，教授，硕士生导师，专业方向：临床医学。E-mail：lxh552@hotmail.com。ORCID：0009-0003-5682-0278
作者简介:张一粟（1997—），男，硕士研究生，专业方向：临床医学。E-mail：1055860873@qq.com。ORCID：0009-0001-4887-3682
基金资助:
蚌埠医科大学研究生科研创新计划项目“基于海马区BDNF表达和GSK-3磷酸化交互作用探讨艾司氯胺酮对小鼠围生期疼痛-抑郁共病的作用和机制”(Byycx22098)

Establishment and Evaluation of Mouse Model of Pregnancy Pain-depression Comorbidity Induced by Chronic Unpredictable Stress, Complete Freund's Adjuvant and Formalin

Yisu ZHANG¹^,²(), Xinru LIU¹^,², Ruojie WU¹^,², Rui LIU¹^,², Hong OUYANG², Xiaohong LI¹()()

^1.Department of Anesthesiology, The First Affiliated Hospital of Bengbu Medical University ; Bengbu 233000, China
^2.Graduate School of Bengbu Medical University, Bengbu 233000, China

Received:2024-01-10 Revised:2024-05-09 Published:2024-06-25 Online:2024-06-25
Correspondence to: LI Xiaohong (ORCID: 0009-0003-5682-0278), E-mail: lxh552@hotmail.com

摘要/Abstract

摘要：

目的通过慢性不可预知性应激（chronic unpredictable stress，CUS）联合完全弗氏佐剂（complete Freund's adjuvant，CFA）和福尔马林诱导建立妊娠期疼痛-抑郁共病小鼠动物模型，对其相关表型进行系统评价，并初步探究其共病的病理基础。方法选择8周龄的C57BL/6J雌性小鼠，依据糖水偏好实验数据，采用随机分层方法将其分为对照组（妊娠前不干预）和CUS组（妊娠前予以CUS干预）。CUS造模完成后，将雌雄小鼠合笼配对，妊娠期小鼠分别于右后肢足底皮下注射50% CFA和5%福尔马林溶液，诱导建立妊娠期疼痛-抑郁共病小鼠模型。实验共分8组，即为对照-空白组、CUS-空白组、对照-CFA组、CUS-CFA组、对照-福尔马林组、CUS-福尔马林组、对照-CFA+福尔马林组、CUS-CFA+福尔马林组，每组10只。各组小鼠均在CUS干预前后、妊娠后和分娩后，通过糖水偏好实验、强迫游泳实验、悬尾实验和旷场实验评价行为学变化，并通过机械刺痛实验和热辐射痛实验测定各组小鼠对痛觉的敏感性变化；最后处死小鼠，用酶联免疫吸附法检测各组小鼠海马体中白细胞介素-6（interleukin-6，IL-6）、肿瘤坏死因子α（tumor necrosis factor-α，TNF-α），以及血清皮质醇（cortisol）和促肾上腺皮质激素（adrenocorticotropic hormone，ACTH）的含量。结果与对照-空白组相比，CUS-空白组模型小鼠产生了明显的抑郁样行为，并伴随痛阈明显降低（P＜0.001）。与对照-空白组相比，对照-CFA+福尔马林组在CFA注射与福尔马林注射后均出现痛阈下降（P＜0.01）。与对照-空白组和对照-福尔马林组相比，CUS-福尔马林组的痛阈明显降低（P＜0.01），且三者依次下降。与对照-空白组和对照-CFA组相比，CUS-CFA组的痛阈明显降低（P＜0.001），且三者依次下降。与对照-空白组、对照-CFA+福尔马林组相比，CUS-CFA+福尔马林组小鼠的机械痛阈显著降低（P＜0.001）且三者依次下降，热辐射耐受时间缩短（P＜0.01）且三者依次缩短。与对照-CFA+福尔马林组和CUS-空白组小鼠相比，CUS-CFA+福尔马林组小鼠的糖水偏好百分比显著降低（P＜0.001），强迫游泳时不动时间显著延长（P＜0.001），悬尾时不动时间也显著延长（P＜0.001），在旷场中央探索的时间显著缩短（P＜0.001），旷场探索总路程显著缩短（P＜0.001），中央探索路程占比减少（P＜0.001）。与对照-CFA+福尔马林组和CUS-空白组相比，CUS-CFA+福尔马林组小鼠血清皮质醇和ACTH水平显著升高（P＜0.01），海马体中IL-6、TNF-α水平升高（P＜0.05）。结论 CUS联合CFA和福尔马林注射可作为建立妊娠期疼痛-抑郁共病C57BL/6J小鼠模型的理想方法。该模型小鼠的行为学改变可能是通过调节海马区的炎症反应水平和下丘脑-垂体-肾上腺（hypothalamic–pituitary–adrenal，HPA）轴的激素水平导致的。

关键词: 妊娠期抑郁, 疼痛, 共病, 炎症因子, 下丘脑-垂体-肾上腺轴, C57BL/6J小鼠

Abstract:

Objective To establish a mouse model of pregnancy pain-depression comorbidity induced by chronic unpredictable stress (CUS), complete Freund's adjuvant (CFA), and formalin, and to systematically evaluate the associated phenotypes and preliminarily explore the pathological basis of the comorbidity. Methods Eight-week-old C57BL/6J female mice were randomly strarified divided into a control group (no intervention before pregnancy) and a CUS model group (CUS intervention before pregnancy) based on sucrose preference test (SPT) data. After completing the CUS treatment, female and male mice were paired and mated. Pain was induced by injecting 50% CFA and 5% formalin in the right hind foot during pregnancy to create a model of pregnancy pain-depression comorbidity. The experiment was divided into 8 subgroups: control-blank group, CUS-blank group, control-CFA group, CUS-CFA group, control-formalin group, CUS-formalin group, control-CFA+formalin group, and CUS-CFA+formalin group, with 10 mice in each group. The mice in each group were subject to behavioral tests, including the SPT, forced swimming test, tail suspension test, and open field test before and after CUS intervention, during pregnancy, and after delivery. Pain sensitivity changes were measured using mechanical allodynia and thermal hyperalgesia tests. Mice were then euthanized. Levels of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in hippocampus, as well as cortisol and adrenocorticotropic hormone (ACTH) in serum, were detected by enzyme-linked immunosorbent assay (ELISA). Results Compared with the control-blank group, the CUS-blank group showed a significant depression-like behavior with reduced pain threshold (P<0.001). The control-CFA+formalin group showed a decrease in pain threshold after both CFA injection and formalin injection (P<0.01). Compared with the control-blank and control-formalin groups, the pain threshold was significantly lower in the CUS-formalin group (P<0.01), with a sequential decrease among the three. Compared with the control-blank and control-CFA groups, the pain threshold was significantly lower in the CUS-CFA group (P<0.001), with a sequential decrease among the three. Compared with the control-blank and control-CFA+formalin groups, the mechanical pain threshold of mice in the CUS-CFA+formalin group was significantly lower (P<0.001) and the thermal radiation tolerance time was shorter (P<0.01), both with sequential decreases among the three. Compared with the control-CFA+formalin and the CUS-blank groups, the CUS-CFA+formalin group had a significantly lower percentage of sucrose preference (P<0.001), longer immobility time during the forced swimming test (P<0.001) and tail suspension test (P<0.001), reduced central exploration time in the open field test (P<0.001), reduced total exploration distance (P<0.001), and reduced percentage of distance traveled for central exploration (P<0.001). Compared with the control-CFA+formalin and CUS-blank groups, the serum cortisol and ACTH levels of the CUS-CFA+formalin group were significantly higher (P<0.01), and the levels of IL-6 and TNF-α in the hippocampus were higher (P<0.05). Conclusion The combination of CUS+CFA+formalin injections is an ideal method for establishing a C57BL/6J mouse model of pregnancy pain-depression comorbidity. The behavioral changes in model mice may be attributed to the regulation of inflammatory response in hippocampus and hormone levels in the hypothalamic-pituitary-adrenal (HPA) axis.

Key words: Pregnancy depression, Pain, Comorbidity, Inflammatory factors, Hypothalamic-pituitary-adrenal axis, C57BL/6J mice

中图分类号:

R-332

张一粟,刘欣茹,武若杰,等. 慢性不可预知性应激与完全弗氏佐剂、福尔马林诱导的妊娠期疼痛-抑郁共病小鼠模型的构建与评价[J]. 实验动物与比较医学, 2024, 44(3): 259-269. DOI: 10.12300/j.issn.1674-5817.2024.005.

Yisu ZHANG,Xinru LIU,Ruojie WU,et al. Establishment and Evaluation of Mouse Model of Pregnancy Pain-depression Comorbidity Induced by Chronic Unpredictable Stress, Complete Freund's Adjuvant and Formalin[J]. Laboratory Animal and Comparative Medicine, 2024, 44(3): 259-269. DOI: 10.12300/j.issn.1674-5817.2024.005.

图/表 6

注：CUS，慢性不可预知性应激；CFA，完全弗氏佐剂；SPT，糖水偏好实验；FST，强迫游泳实验；TST，悬尾实验；OFT，旷场实验；PTT，痛阈实验；T0，CUS干预前；T4，CUS干预后；T8，妊娠后。
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图1 小鼠妊娠期抑郁-疼痛共病模型构建的实验流程图
注：CUS，慢性不可预知性应激；CFA，完全弗氏佐剂；SPT，糖水偏好实验；FST，强迫游泳实验；TST，悬尾实验；OFT，旷场实验；PTT，痛阈实验；T0，CUS干预前；T4，CUS干预后；T8，妊娠后。

Figure 1 Experimental flowchart for the construction of a depression-pain comorbidity model in pregnant mice
Note： CUS, chronic unpredictable stress; CFA, complete Freund's adjuvant; SPT, sucrose preference test; FST, forced swimming test; TST, tail suspension test; OFT, open field test; PTT, pain threshold test; T0, before CUS intervention; T4, after CUS intervention; T8, after pregnancy.

注：A，对照组（n=40）和慢性不可预知性应激（CUS）组（n=40）干预第0（T0）、1（T1）、2（T2）、3（T3）和4（T4）周末的糖水偏好实验结果；B，各组干预第0（T0）和4（T4）周末的游泳不动时间；C，各组干预第0（T0）和4（T4）周末的悬尾不动时间；D，各组干预第0（T0）和4（T4）周末的旷场中央探索时间占比；E，各组干预第0（T0）、4（T4）周末的右后足刺痛阈值；F，各组干预第0（T0）、4（T4）周末的右后足热辐射痛耐受时间。^ns差异无统计学意义，^*P＜0.05，^**P＜0.01，^***P＜0.001，n=40。
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图2 CUS模型小鼠的抑郁行为学评价及痛阈检测结果
注：A，对照组（n=40）和慢性不可预知性应激（CUS）组（n=40）干预第0（T0）、1（T1）、2（T2）、3（T3）和4（T4）周末的糖水偏好实验结果；B，各组干预第0（T0）和4（T4）周末的游泳不动时间；C，各组干预第0（T0）和4（T4）周末的悬尾不动时间；D，各组干预第0（T0）和4（T4）周末的旷场中央探索时间占比；E，各组干预第0（T0）、4（T4）周末的右后足刺痛阈值；F，各组干预第0（T0）、4（T4）周末的右后足热辐射痛耐受时间。^ns差异无统计学意义，^*P＜0.05，^**P＜0.01，^***P＜0.001，n=40。

Figure 2 Depressive behavior evaluation and pain threshold detection in the CUS model of mice
Note： A, Results of the sucrose preference test at the end of intervention periods before the start of the experiment (T0), one week after the experiment (T1), two weeks after the experiment (T2), three weeks after the experiment (T3), and four weeks after the experiment (T4) for the control group (n=40) and the chronic unpredictable stress (CUS) group (n=40); B, Forced swimming immobility time at the end of intervention periods T0 and T4 for each group; C, Tail suspension immobility time at the end of intervention periods T0 and T4 for each group; D, Percentage of time spent exploring the center of an open field for each group at the end of intervention periods T0 and T4; E, Right hind foot stabbing pain thresholds for each group at the end of intervention periods T0 and T4; F, Time to tolerate thermal radiation pain in the right hind foot for each group at the end of intervention T0 and T4. ^nsdifferences were not statistically significant, ^*P＜0.05, ^**P＜0.01, ^***P＜0.001, n=40.

注：对照-空白组即未经任何处理；对照-A组即未经慢性不可预知性应激（CUS）但注射福尔马林；CUS-A组即经CUS刺激且注射福尔马林；对照-C组即未经CUS但注射完全弗氏佐剂（CFA）；CUS-C组即经CUS刺激且注射CFA；对照-A+C组即未经CUS但注射福尔马林和CFA；CUS-空白组即经CUS刺激但未经福尔马林和CFA注射；CUS-A+C组即经CUS刺激且注射福尔马林和CFA。A，对照-空白组、对照-A组、CUS-A组小鼠分娩后（T8）的右后足底刺痛阈值；B，对照-空白组、对照-C组、CUS-C组小鼠妊娠第2周末（T6）的足底刺痛阈值；C，对照-C组和CUS-C组小鼠妊娠2周末（T6）和分娩后（T8）的足底刺痛阈值；D，对照-空白组、对照-A+C组、CUS-空白组、CUS-A+C组小鼠经CUS干预前（T0）、CUS干预后（T4）、妊娠第2周末（T6）、分娩后（T8）的足底刺痛阈值；E，对照-空白组、对照-A+C组和CUS-A+C组小鼠分娩后（T8）的足底刺痛阈值；F，对照-空白组、对照-A+C组和CUS-A+C组小鼠分娩后（T8）的足底热辐射耐受时间。^ns差异无统计学意义，^**P＜0.01，^***P＜0.001，n=10。
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图3 抑郁对妊娠期小鼠感知疼痛的能力产生影响
注：对照-空白组即未经任何处理；对照-A组即未经慢性不可预知性应激（CUS）但注射福尔马林；CUS-A组即经CUS刺激且注射福尔马林；对照-C组即未经CUS但注射完全弗氏佐剂（CFA）；CUS-C组即经CUS刺激且注射CFA；对照-A+C组即未经CUS但注射福尔马林和CFA；CUS-空白组即经CUS刺激但未经福尔马林和CFA注射；CUS-A+C组即经CUS刺激且注射福尔马林和CFA。A，对照-空白组、对照-A组、CUS-A组小鼠分娩后（T8）的右后足底刺痛阈值；B，对照-空白组、对照-C组、CUS-C组小鼠妊娠第2周末（T6）的足底刺痛阈值；C，对照-C组和CUS-C组小鼠妊娠2周末（T6）和分娩后（T8）的足底刺痛阈值；D，对照-空白组、对照-A+C组、CUS-空白组、CUS-A+C组小鼠经CUS干预前（T0）、CUS干预后（T4）、妊娠第2周末（T6）、分娩后（T8）的足底刺痛阈值；E，对照-空白组、对照-A+C组和CUS-A+C组小鼠分娩后（T8）的足底刺痛阈值；F，对照-空白组、对照-A+C组和CUS-A+C组小鼠分娩后（T8）的足底热辐射耐受时间。^ns差异无统计学意义，^**P＜0.01，^***P＜0.001，n=10。

Figure 3 Depression affects the ability to perceive pain in pregnant mice
Note： Control-blank group, i.e., without any treatment; Control-A group, i.e., without chronic unpredictable stress (CUS) but injected with formalin; CUS-A group, i.e., stimulated by CUS and injected with formalin; Control-C group, i.e., without CUS but injected with complete Freund's adjuvant (CFA); CUS-C group, i.e., stimulated by CUS and injected with CFA; Control-A+C group, i.e., without CUS but injected with formalin and CFA; CUS-blank group, i.e., stimulated by CUS but not injected with formalin and CFA; and CUS-A+C group, i.e., stimulated by CUS and injected with formalin and CFA. A, Pain threshold of the right hind foot in the control-blank, control-A, and CUS-A groups after delivery (T8); B, Pain threshold of the right hind foot at the end of gestation week 2 (T6) in the control-blank, control-C, and CUS-C groups; C, Pain threshold of the right hind foot at the end of gestation week 2 (T6) and after delivery (T8) in the control-C and CUS-C groups; D, Pain threshold of the right hind foot in control-blank, control-A+C, CUS-blank, and CUS-A+C mice before the CUS intervention (T0), after the CUS intervention (T4), at the end of the 2nd week of gestation (T6), and after delivery (T8); E, Pain threshold of the right hind foot after delivery (T8) of mice in the control-blank, control-A+C, and CUS-A+C groups; F, Plantar thermal radiation tolerance time of the right hind foot after delivery (T8) in control-blank, control-A+C, and CUS-A+C groups. ^nsdifferences were not statistically significant, ^**P＜0.01, ^***P＜0.001, n=10.

注：对照-A+C组即未经慢性不可预知性应激（CUS）但注射福尔马林和完全弗氏佐剂（CFA）；CUS-空白组即经CUS刺激但未经福尔马林和CFA注射；CUS-A组即经CUS刺激且注射福尔马林；CUS-C组即经CUS刺激且注射CFA；CUS-A+C组即经CUS刺激且注射福尔马林和CFA。A～D，各组小鼠分娩后（T8）的糖水偏好度、游泳不动时间、悬尾不动时间和旷场中央探索时间占比。^**P＜0.01，^***P＜0.001，n=10。
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图4 妊娠期疼痛对小鼠抑郁行为产生影响
注：对照-A+C组即未经慢性不可预知性应激（CUS）但注射福尔马林和完全弗氏佐剂（CFA）；CUS-空白组即经CUS刺激但未经福尔马林和CFA注射；CUS-A组即经CUS刺激且注射福尔马林；CUS-C组即经CUS刺激且注射CFA；CUS-A+C组即经CUS刺激且注射福尔马林和CFA。A～D，各组小鼠分娩后（T8）的糖水偏好度、游泳不动时间、悬尾不动时间和旷场中央探索时间占比。^**P＜0.01，^***P＜0.001，n=10。

Figure 4 Pain during pregnancy impacts depressive behaviors of mice
Note： Control-A+C group, i.e., without chronic unpredictable stress (CUS) but injected with formalin and complete Freund's adjuvant (CFA); CUS-blank group, i.e., stimulated with CUS but not injected with formalin and CFA; CUS-A group, i.e., stimulated with CUS and injected with formalin; CUS-C group, i.e., stimulated with CUS and injected with CFA; CUS-A+C group, i.e., stimulated with CUS and injected with formalin and CFA. A-D, Preference for sugar water, swimming immobility time, tail suspension immobility time, and center exploration time in an open field as a percentage of time in each group after delivery (T8). ^**P＜0.01, ^***P＜0.001, n=10.

注：对照-空白组即未经任何处理；对照-A+C组即未经慢性不可预知性应激（CUS）但注射福尔马林和完全弗氏佐剂（CFA）；CUS-空白组即经CUS刺激但未经福尔马林和CFA注射；CUS-A+C组即经CUS刺激且注射福尔马林和CFA。A~D，对照-空白组、对照-A+C组、CUS-空白组和CUS-A+C组小鼠分娩后（T8）的旷场实验轨迹及热力图；E~F，各组小鼠分娩后（T8）的旷场探索总路程和中央探索路程占比。^**P＜0.01, ^***P＜0.001, n=10。
">

图5 各组代表性旷场轨迹与热力图
注：对照-空白组即未经任何处理；对照-A+C组即未经慢性不可预知性应激（CUS）但注射福尔马林和完全弗氏佐剂（CFA）；CUS-空白组即经CUS刺激但未经福尔马林和CFA注射；CUS-A+C组即经CUS刺激且注射福尔马林和CFA。A~D，对照-空白组、对照-A+C组、CUS-空白组和CUS-A+C组小鼠分娩后（T8）的旷场实验轨迹及热力图；E~F，各组小鼠分娩后（T8）的旷场探索总路程和中央探索路程占比。^**P＜0.01, ^***P＜0.001, n=10。

Figure 5 Representative open field trajectory maps and heat maps for each group
Note： Control-blank group, i.e., without any treatment; control-A+C group, i.e., without chronic unpredictable stress (CUS) but injected with formalin and complete Freund's adjuvant (CFA); CUS-blank group, i.e., stimulated with CUS but not injected with formalin and CFA; and CUS-A+C group, i.e., stimulated with CUS and injected with formalin and CFA. A-D, Trajectory maps and heat maps of open field test in Control-blank, Control-A+C, CUS-blank, and CUS-A+C mice after delivery (T8); E-F, Ratio of central exploration distance to total distance after delivery (T8) in each group of mice. ^**P＜0.01, ^***P＜0.001, n=10.

注：对照-空白组即未经任何处理；对照-A+C组即未经慢性不可预知性应激（CUS）但注射福尔马林和完全弗氏佐剂（CFA）；CUS-空白组即经CUS刺激但未经福尔马林和CFA注射；CUS-A+C组即经CUS刺激且注射福尔马林和CFA。A～D，各组小鼠血清皮质醇和ACTH水平，以及海马体IL-6和TNF-α水平。^**P＜0.01，^***P＜0.001， n=10。
">

图6 妊娠期抑郁-疼痛共病小鼠下丘脑-垂体-肾上腺轴（HPA轴）激素水平和海马体炎症因子水平更高
注：对照-空白组即未经任何处理；对照-A+C组即未经慢性不可预知性应激（CUS）但注射福尔马林和完全弗氏佐剂（CFA）；CUS-空白组即经CUS刺激但未经福尔马林和CFA注射；CUS-A+C组即经CUS刺激且注射福尔马林和CFA。A～D，各组小鼠血清皮质醇和ACTH水平，以及海马体IL-6和TNF-α水平。^**P＜0.01，^***P＜0.001， n=10。

Figure 6 Higher hypothalamic-pituitary-adrenal axis （HPA axis） hormone levels and hippocampal inflammatory factor levels in mice with depression-pain comorbidity during pregnancy
Note： Control-blank group, i.e., without any treatment; Control-A+C group, i.e., without chronic unpredictable stress (CUS) but injected with formalin and complete Freund's adjuvant (CFA); CUS-blank group, i.e., stimulated with CUS but not injected with formalin and CFA; and CUS-A+C group, i.e., stimulated with CUS and injected with formalin and CFA. A-D, Serum cortisol and ACTH levels, as well as hippocampal IL-6 and TNF-α levels, in mice from each group. ^**P＜0.01, ^***P＜0.001, n=10.

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慢性不可预知性应激与完全弗氏佐剂、福尔马林诱导的妊娠期疼痛-抑郁共病小鼠模型的构建与评价

Establishment and Evaluation of Mouse Model of Pregnancy Pain-depression Comorbidity Induced by Chronic Unpredictable Stress, Complete Freund's Adjuvant and Formalin

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