本研究探讨了对于幸存的败血症患者而言，后遗症与严重创伤后应激障碍（PTSD）之间的关联。本研究使用大鼠幸存败血症作为PTSD模型，检测了在败血症初始阶段靶向内皮素-1（ET-1）/大麻素系统和神经胶质激活的干预对于恐惧记忆的泛化的影响。我们首先评估了恐惧条件化前的痛觉增敏作为对照组。通过盲肠结扎和穿刺（CLP）的方法诱导大鼠的败血症。接受一个或三次穿刺的CLP诱导的败血症使幸存者在CLP程序后的13和20天出现了恐惧泛化现象，而这个过程与痛觉增敏无关。败血症动物在CLP后4小时胼胝体脑室内给予车辆、内皮素A受体（ETA）拮抗剂BQ123、大麻素CB1和CB2受体拮抗剂AM251和AM630以及神经胶质阻断剂米诺环素进行处理。CB1或ETA受体的阻断可以增加幸存率，但只有前者可以逆转恐惧记忆的泛化。内皮素系统的阻断对于改善幸存率而言很重要，但对于恐惧记忆并不重要。CB2受体拮抗剂或米诺环素的治疗也可以逆转恐惧记忆的泛化，但不会提高与CLP相关的幸存率。米诺环素的治疗还可以降低海马中肿瘤坏死因子-α水平，这表明神经炎症对于CLP引起的恐惧记忆泛化很重要。CLP对于恐惧记忆的泛化影响与弓状核蛋白表达无关，弓状核蛋白是突触可塑性的调节因子。Copyright © 2023 Elsevier B.V. 版权所有。

Sepsis is associated with several comorbidities in survivors, such as posttraumatic stress disorder (PTSD). This study investigated whether rats that survive sepsis develop the generalization of fear memory as a model of PTSD. Responses to interventions that target the endothelin-1 (ET-1)/cannabinoid system and glial activation in the initial stages of sepsis were evaluated. As a control, we evaluated hyperalgesia before fear conditioning. Sepsis was induced by cecal ligation and puncture (CLP) in Wistar rats. CLP-induced sepsis with one or three punctures resulted in fear generalization in the survivors 13 and 20 days after the CLP procedure, a process that was not associated with hyperalgesia. Septic animals were intracerebroventricularly treated with vehicle, the endothelin receptor A (ETA) antagonist BQ123, the cannabinoid CB1 and CB2 receptor antagonists AM251 and AM630, respectively, and the glial blocker minocycline 4 h after CLP. The blockade of either CB1 or ETA receptors increased the survival rate, but only the former reversed fear memory generalization. The endothelinergic system blockade is important for improving survival but not for fear memory. Treatment with the CB2 receptor antagonist or minocycline also reversed the generalization of fear memory but did not increase the survival rate that was associated with CLP. Minocycline treatment also reduced tumor necrosis factor-α levels in the hippocampus suggesting that neuroinflammation is important for the generalization of fear memory induced by CLP. The influence of CLP on the generalization of fear memory was not related to Arc protein expression, a regulator of synaptic plasticity, in the dorsal hippocampus.Copyright © 2023 Elsevier B.V. All rights reserved.