芬太尼对应激模型新生大鼠学习记忆功能的影响及其分子机制

Recently the influence of anesthetics on the learning and memory function of infants and children has been paid more and more attention by the global anesthesiologists. This project using the free period rat model of stress and pain stress in brain development, cytology, molecular, in experiment three aspects to fully explore the effects of fentanyl on brain development and its molecular mechanism. The study includes: in vitro culture of primary neurons in the body, no stress rat model on fentanyl induced brain injury or cell apoptosis and influence differentiation of neurons, molecular target, effect on learning and memory in adulthood; explore the fentanyl inhibit the hypothalamic pituitary adrenal axis and immune factors, level of protection neuronal cells against targets of excessive stress injury in a rat model of pain stress, and memory effects on adult learning, the comprehensive evaluation of fentanyl on the developing brains of rational use of drugs. In this study the rat model of Brennan paw incision pain stress brain development was used to simulate the real stress state during and after surgery, therefore the conclusion of the study have clinical guiding significance.

近年来麻醉药是否会影响或损害婴幼儿及儿童的学习记忆功能日益受到全球麻醉医生的关注，本项目分别采用无应激及疼痛应激脑发育期大鼠模型，在细胞学、分子学、大体实验三方面全面探索芬太尼对发育期大脑的影响及分子机制。研究要点包括：在离体培养原代神经元细胞、在体无应激大鼠模型上探究芬太尼致脑细胞损伤或凋亡及影响神经元定向分化的程度、分子作用靶点、对成年后学习记忆影响；在疼痛应激大鼠模型上探究芬太尼抑制下丘脑-垂体-肾上腺轴及免疫因子水平、保护神经元细胞免受过度应激损伤的作用靶点，及对成年后学习记忆影响，由此综合评判芬太尼对发育期大脑的用药合理性。本研究采用Brennan爪切口疼痛应激脑发育期大鼠模型，更能模拟真实的术中和术后应激状态，具有临床指导意义。

多项研究表明，幼年多次接触麻醉和手术的儿童发生学习障碍的风险增加。七氟烷和芬太尼都是临床上常用的麻醉药物，幼年时期大剂量使用七氟烷看可造成大脑神经元凋亡，外源性阿片类药物也可造成海马神经元凋亡从而影响学习和记忆。线粒体在细胞凋亡中也起着核心作用，线粒体外膜透性(MOMP)增加可能会导致细胞死亡，凋亡信号通路下游涉及线粒体细胞色素C释放和随后的caspase活化。本研究拟通过小鼠幼年期多次麻醉模型，运用透射电镜、蛋白免疫印迹、免疫组化、免疫荧光、行为学等方法，深入研究幼年期多次使用七氟烷和芬太尼是否造成神经元凋亡和线粒体的改变，以及成年后小鼠学习记忆能力的影响，为临床合理用药提供理论依据。