Persistent inflammatory pain is linked with anxiety-like behaviors, increased blood corticosterone, and reduced global DNA methylation in the rat amygdala.
Persistent inflammatory pain is linked with anxiety-like behaviors, increased blood corticosterone, and reduced global DNA methylation in the rat amygdala.
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DOI：
10.1177/17448069221121307
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发表时间：
2022-04
期刊：
影响因子：
3.3
通讯作者：
Leite-Panissi, Christie R. A.
中科院分区：
文献类型：
--
作者：
Spinieli, Richard L.;Cazuza, Rafael Alves;Sales, Amanda Juliana;Gomes Carolino, Ruither Oliveira;Martinez, Diana;Anselmo-Franci, Janete;Tajerian, Maral;Leite-Panissi, Christie R. A.
关键词：
慢性疼痛会增加患焦虑症的风险，边缘区域可能是神经基础。尽管有很高的临床相关性，但在持续性疼痛的背景下，对焦虑的确切行为、激素和脑神经可塑性相关性知之甚少。先前的研究表明，慢性疼痛模型中伤害性阈值的降低与大鼠的焦虑样行为平行，但关于其对应激反应和循环皮质酮水平的影响存在相互矛盾的观点。对大脑编码疼痛相关焦虑的分子机制更是知之甚少。这项研究考察了大鼠模型中持续的炎症性疼痛如何影响焦虑样行为和皮质酮释放，以及这些变化是否会反映在参与应激调节的大脑区域的全局DNA甲基化水平上。成年雄性Wistar大鼠右后掌注射完全弗氏佐剂(CFA)或生理盐水。行为测试包括伤害性阈值(数字麻醉仪)、运动功能(开场测试)和焦虑样行为(高架+迷宫和暗光盒测试)。用放射免疫法测定皮质酮。对杏仁核、前额叶皮质和腹侧海马区的整体DNA甲基化(酶免疫分析)和DNMT3a水平(Western Blotting)进行了量化。在没有运动异常的情况下，CFA给药导致伤害性阈值持续降低。在高架Plus迷宫中观察到焦虑样行为增加，并在疼痛诱导后10天伴随血皮质酮水平上升。杏仁核的整体DNA甲基化减少，在所研究的任何区域DNMT3a的丰度都没有变化。持续性炎性疼痛通过杏仁核DNA甲基化促进焦虑样行为、HPA轴激活和表观遗传调节。这些发现描述了在一个特征良好的啮齿动物模型中将疼痛和压力联系起来的分子机制。
Chronic pain increases the risk of developing anxiety, with limbic areas being likely neurological substrates. Despite high clinical relevance, little is known about the precise behavioral, hormonal, and brain neuroplastic correlates of anxiety in the context of persistent pain. Previous studies have shown that decreased nociceptive thresholds in chronic pain models are paralleled by anxiety-like behavior in rats, but there are conflicting ideas regarding its effects on the stress response and circulating corticosterone levels. Even less is known about the molecular mechanisms through which the brain encodes pain-related anxiety. This study examines how persistent inflammatory pain in a rat model would impact anxiety-like behaviors and corticosterone release, and whether these changes would be reflected in levels of global DNA methylation in brain areas involved in stress regulation. Complete Freund’s adjuvant (CFA) or saline was administered in the right hindpaw of adult male Wistar rats. Behavioral testing included the measurement of nociceptive thresholds (digital anesthesiometer), motor function (open field test), and anxiety-like behaviors (elevated plus maze and the dark-light box test). Corticosterone was measured via radioimmunoassay. Global DNA methylation (enzyme immunoassay) as well as DNMT3a levels (western blotting) were quantified in the amygdala, prefrontal cortex, and ventral hippocampus. CFA administration resulted in persistent reduction in nociceptive threshold in the absence of locomotor abnormalities. Increased anxiety-like behaviors were observed in the elevated plus maze and were accompanied by increased blood corticosterone levels 10 days after pain induction. Global DNA methylation was decreased in the amygdala, with no changes in DNMT3a abundance in any of the regions examined. Persistent inflammatory pain promotes anxiety -like behaviors, HPA axis activation, and epigenetic regulation through DNA methylation in the amygdala. These findings describe a molecular mechanism that links pain and stress in a well-characterized rodent model.
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