Effect of acetyl-L-carnitine on hypersensitivity in acute recurrent caerulein-induced pancreatitis and microglial activation along the brain's pain circuitry.
Effect of acetyl-L-carnitine on hypersensitivity in acute recurrent caerulein-induced pancreatitis and microglial activation along the brain's pain circuitry.
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DOI：
10.3748/wjg.v27.i9.794
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发表时间：
2021-03-07
影响因子：
4.3
通讯作者：
Westlund KN
中科院分区：
文献类型：
--
作者：
McIlwrath SL;Starr ME;High AE;Saito H;Westlund KN
急性胰腺炎（AP）和复发性AP是严重的卫生保健问题，由于脓毒症导致极度疼痛和潜在的致命后果。经验证的雨蛙肽-（CAE）诱导的急性/复发AP的小鼠模型产生用于研究的继发性持续性超敏反应和焦虑样行为变化。确定乙酰-L-卡尼汀（ALC）减少CAE-胰腺炎疼痛相关行为和沿着疼痛回路的脑小胶质细胞激活的疗效。用6 hly腹腔内（i. p.）注射CAE（50 μg/kg），每周3天，持续6周。从第4周开始，小鼠接受媒介物或ALC直至实验结束。机械超敏反应用von Frey细丝进行评估。用热板试验测定热过敏性。在第6周，使用高架十字迷宫和旷场测试来测试类迷宫行为。通过对离子化钙结合接头分子1（Iba 1）进行免疫染色，在组织学上定量脑中的小胶质细胞活化。患有CAE诱导的胰腺炎的小鼠具有显著降低的机械退缩阈值和热反应潜伏期，表明持续的疼痛。ALC治疗减弱了炎症诱导的超敏反应，但由于重复腹腔内注射引起的腹壁损伤引起的超敏反应持续存在。与对照组相比，胰腺炎动物在高架十字迷宫中表现出自发的焦虑样行为。ALC治疗导致直立活动事件数量增加，但用于“安全性”的时间没有改变。在所有腹部注射后，如果在实验结束时切除胰腺，则胰腺是半透明的，如果在第二天切除胰腺，则胰腺是不透明的，表明自发愈合。对天狼星红和坚牢绿色染色的胰腺切片进行的尸检组织病理学分析发现，患有CAE诱导胰腺炎的小鼠切片中存在广泛的纤维化和腺泡细胞萎缩，这些胰腺炎未通过ALC治疗得到挽救。与未处理对照组相比，CAE诱导胰腺炎小鼠的海马、丘脑（板内核）、下丘脑和杏仁核中小胶质细胞Iba 1免疫染色显著增加，但与未处理对照组相比，初级躯体感觉皮层中小胶质细胞Iba 1免疫染色无变化。CAE诱导的胰腺炎引起疼痛相关行为、胰腺纤维化和脑小胶质细胞变化增加。ALC减轻了CAE诱导的机械和热过敏，但不能减轻重复注射引起的腹壁损伤诱导的过敏。
Acute pancreatitis (AP) and recurring AP are serious health care problems causing excruciating pain and potentially lethal outcomes due to sepsis. The validated caerulein- (CAE) induced mouse model of acute/recurring AP produces secondary persistent hypersensitivity and anxiety-like behavioral changes for study. To determine efficacy of acetyl-L-carnitine (ALC) to reduce pain-related behaviors and brain microglial activation along the pain circuitry in CAE-pancreatitis. Pancreatitis was induced with 6 hly intraperitoneal (i.p.) injections of CAE (50 µg/kg), 3 d a week for 6 wk in male C57BL/6J mice. Starting in week 4, mice received either vehicle or ALC until experiment’s end. Mechanical hyper-sensitivity was assessed with von Frey filaments. Heat hypersensitivity was determined with the hotplate test. Anxiety-like behavior was tested in week 6 using elevated plus maze and open field tests. Microglial activation in brain was quantified histologically by immunostaining for ionized calcium-binding adaptor molecule 1 (Iba1). Mice with CAE-induced pancreatitis had significantly reduced mechanical withdrawal thresholds and heat response latencies, indicating ongoing pain. Treatment with ALC attenuated inflammation-induced hypersensitivity, but hypersensitivity due to abdominal wall injury caused by repeated intraperitoneal injections persisted. Animals with pancreatitis displayed spontaneous anxiety-like behavior in the elevated plus maze compared to controls. Treatment with ALC resulted in increased numbers of rearing activity events, but time spent in “safety” was not changed. After all the abdominal injections, pancreata were translucent if excised at experiment’s end and opaque if excised on the subsequent day, indicative of spontaneous healing. Post mortem histopathological analysis performed on pancreas sections stained with Sirius Red and Fast Green identified wide-spread fibrosis and acinar cell atrophy in sections from mice with CAE-induced pancreatitis that was not rescued by treatment with ALC. Microglial Iba1 immunostaining was significantly increased in hippocampus, thalamus (intralaminar nuclei), hypothalamus, and amygdala of mice with CAE-induced pancreatitis compared to naïve controls but unchanged in the primary somatosensory cortex compared to naïves. CAE-induced pancreatitis caused increased pain-related behaviors, pancreatic fibrosis, and brain microglial changes. ALC alleviated CAE-induced mechanical and heat hypersensitivity but not abdominal wall injury-induced hypersensitivity caused by the repeated injections.
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影响因子：
5.3
作者：
Fernández-Arjona MDM;Grondona JM;Granados-Durán P;Fernández-Llebrez P;López-Ávalos MD
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Sherman, Stuart
DOI：
10.1111/j.1742-7843.2009.00399.x
发表时间：
2009-07-01
影响因子：
3.1
作者：
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影响因子：
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作者：
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