Genty Julien, Tetsi Nomigni Milène, Anton Fernand, Hanesch Ulrike
Laboratory of Neurophysiology, Institute for Health and Behavior, University of Luxembourg, 162a, avenue de la Faïencerie, L-1511, Luxembourg, Luxembourg.
Neurobiol Stress. 2017 Nov 24;8:21-32. doi: 10.1016/j.ynstr.2017.11.002. eCollection 2018 Feb.
Early life stress (ELS) leads to a permanent reprogramming of biochemical stress response cascades that may also be relevant for the processing of chronic pain states such as neuropathy. Despite clinical evidence, little is known about ELS-related vulnerability for neuropathic pain and the possibly underlying etiology. In the framework of experimental studies aimed at investigating the respective relationships we used the established ELS model of maternal separation (MS). Rat dams and neonates were separated for 3 h/day from post-natal day 2-12. At adulthood, noxious mechanical and thermal thresholds were assessed before and during induction of neuropathic pain by chronic constriction injury (CCI). The potential involvement of spinal glutamatergic transmission, glial cells, pro-inflammatory cytokines and growth factors was studied by using qPCR. MS did not modify pain thresholds. But, when exposed to neuropathic pain, MS rats exhibited a marked reduction of thermal sensitivity and a delayed development of mechanical allodynia/hyperalgesia when compared to control animals. Also, MS did not alter glucocorticoid receptor mRNA levels, but prevented the CCI-induced down-regulation of NR1 and NR2 sub-units of the NMDA receptor and of the glutamate transporter EAAT3 as observed at 21 days post-surgery. Additionally, CCI-provoked up-regulation of glial cell markers was either prevented (GFAP for astrocytes) or dampened (Iba1 for microglia) by MS. Pro-inflammatory cytokine mRNA expression was either not affected (IL-6) or reduced (IL-1β) by MS shortly after CCI. The growth factors GDNF and NGF were only slightly downregulated 4 days after CCI in the MS-treated animals. The changes in glutamatergic signaling, astroglial and cytokine activation as well as neurotrophin expression could, to some extent, explain these changes in pain behavior. Taken together, the results obtained in the described experimental conditions support the mismatch theory of chronic stress where an early life stress, rather than predisposing individuals to certain pathologies, renders them resilient.
早年生活应激（ELS）会导致生化应激反应级联的永久性重编程，这可能也与诸如神经病变等慢性疼痛状态的处理有关。尽管有临床证据，但对于ELS相关的神经性疼痛易感性以及可能的潜在病因知之甚少。在旨在研究各自关系的实验研究框架中，我们使用了既定的母体分离（MS）ELS模型。从出生后第2天至12天，将大鼠母鼠和新生鼠每天分离3小时。成年后，在通过慢性压迫损伤（CCI）诱导神经性疼痛之前和期间评估有害机械阈值和热阈值。通过定量聚合酶链反应（qPCR）研究脊髓谷氨酸能传递、胶质细胞、促炎细胞因子和生长因子的潜在参与情况。MS并未改变疼痛阈值。但是，与对照动物相比，当暴露于神经性疼痛时，MS大鼠表现出热敏感性明显降低以及机械性异常性疼痛/痛觉过敏的发展延迟。此外，MS并未改变糖皮质激素受体mRNA水平，但可防止手术后21天时观察到的CCI诱导的N-甲基-D-天冬氨酸（NMDA）受体的NR1和NR2亚基以及谷氨酸转运体EAAT3的下调。此外，MS可预防（星形胶质细胞的胶质纤维酸性蛋白（GFAP））或减轻（小胶质细胞的离子钙接头蛋白1（Iba1））CCI引发的胶质细胞标志物上调。CCI后不久，MS对促炎细胞因子mRNA表达要么无影响（白细胞介素6（IL-6））要么降低（白细胞介素1β（IL-1β））。在MS处理的动物中，生长因子胶质细胞源性神经营养因子（GDNF）和神经生长因子（NGF）在CCI后4天仅略有下调。谷氨酸能信号传导、星形胶质细胞和细胞因子激活以及神经营养因子表达的变化在一定程度上可以解释疼痛行为的这些变化。综上所述，在所述实验条件下获得的结果支持慢性应激的失配理论，即早年生活应激并非使个体易患某些疾病，而是使其具有恢复力。
