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
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()(
)
收稿日期:2024-01-10
修回日期:2024-05-09
出版日期:2024-07-06
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:
Yisu ZHANG1,2(), Xinru LIU1,2, Ruojie WU1,2, Rui LIU1,2, Hong OUYANG2, Xiaohong LI1()()
Received:2024-01-10
Revised:2024-05-09
Published:2024-06-25
Online:2024-07-06
Contact:
LI Xiaohong (ORCID: 0009-0003-5682-0278), E-mail: lxh552@hotmail.com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。
中图分类号:
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 miceNote： 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.
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 miceNote： 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.
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 miceNote： 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.
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 miceNote： 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.
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 groupNote： 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.
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 pregnancyNote： 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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