Guo Shufen, Wang Yu, Duan Qingling, Gu Wei, Fu Qun, Ma Zhengliang, Ruan Jiaping
Department of Anesthesiology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.
Department of Anesthesiology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China.
Front Pharmacol. 2024 Sep 3;15:1463339. doi: 10.3389/fphar.2024.1463339. eCollection 2024.
Sress early in life has been linked to visceral hyperalgesia and associated functional gastrointestinal disorders. In a mouse model of visceral hyperalgesia, we investigated whether the EphB2 receptor and its EphrinB2 ligand in spinal cord contribute to dysregulation of glia-neuron interactions.
An established mouse model of stress due to maternal separation (MS). Pups were separated from their mothers for 14 days during early development, then analyzed several weeks later in terms of visceral sensitivity based on the abdominal withdrawal reflex score and in terms of expression of c-fos, EphrinB2, EphB2, and phosphorylated MAP kinases (ERK, p38, JNK).
Visceral hyperalgesia due to MS upregulated EphB2, EphrinB2 and c-fos in the spinal cord, and c-fos levels positively correlated with those of EphB2 and EphrinB2. Spinal astrocytes, microglia, and neurons showed upregulation of EphB2, EphrinB2 and phosphorylated MAP kinases. Blocking EphrinB2/EphB2 signaling in MS mice reduced visceral sensitivity, activation of neurons and glia, and phosphorylation of NMDA receptor. Activating EphrinB2/EphB2 signaling in unstressed mice induced visceral hyperalgesia, upregulation of c-fos, and activation of NMDA receptor similar to maternal separation.
The stress of MS during early development may lead to visceral hyperalgesia by upregulating EphrinB2/EphB2 in the spinal cord and thereby altering neuron-glia interactions.
生命早期的应激与内脏痛觉过敏及相关的功能性胃肠疾病有关。在内脏痛觉过敏的小鼠模型中,我们研究了脊髓中的EphB2受体及其EphrinB2配体是否导致神经胶质细胞与神经元相互作用失调。
建立母鼠分离(MS)所致应激的小鼠模型。幼鼠在早期发育期间与母亲分离14天,然后在数周后根据腹部退缩反射评分分析内脏敏感性,并分析c-fos、EphrinB2、EphB2和磷酸化丝裂原活化蛋白激酶(ERK、p38、JNK)的表达。
MS所致的内脏痛觉过敏使脊髓中的EphB2、EphrinB2和c-fos上调,且c-fos水平与EphB2和EphrinB2水平呈正相关。脊髓星形胶质细胞、小胶质细胞和神经元中EphB2、EphrinB2和磷酸化丝裂原活化蛋白激酶上调。阻断MS小鼠中的EphrinB2/EphB2信号可降低内脏敏感性、神经元和神经胶质细胞的激活以及NMDA受体的磷酸化。在未应激的小鼠中激活EphrinB2/EphB2信号可诱导内脏痛觉过敏、c-fos上调以及NMDA受体激活,类似于母鼠分离。
早期发育期间MS的应激可能通过上调脊髓中的EphrinB2/EphB2,从而改变神经元与神经胶质细胞的相互作用,导致内脏痛觉过敏。