Alterations in the BDNF-mTOR Signaling Pathway in the Spinal Cord Contribute to Hyperalgesia in a Rodent Model of Chronic Restraint Stress
Alterations in the BDNF-mTOR Signaling Pathway in the Spinal Cord Contribute to Hyperalgesia in a Rodent Model of Chronic Restraint Stress
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DOI：
10.1016/j.neuroscience.2019.03.052
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发表时间：
2019-06-15
期刊：
影响因子：
3.3
通讯作者：
Xu, Hui
中科院分区：
文献类型：
--
作者：
Huang, Niannian;Yang, Chun;Xu, Hui
应激是身体对强烈的内外环境刺激的一种非特异性的、系统性的生理反应。越来越多的证据表明，压力，特别是慢性束缚应激(CRS)，可以降低痛阈值，增加疼痛敏感性。然而，CRS的发病和治疗机制仍不清楚。在此，我们旨在研究脑源性神经营养因子(BDNF)-哺乳动物雷帕霉素靶点(MTOR)信号通路在CRS诱导的异常疼痛敏感性中的作用。造模7d后，成功复制大鼠CRS模型，测定动物的缩足机械阈值(PWMT)和甩尾潜伏期(TFL)。CRS显着改变扣带回皮质和脊髓前部BDNF和mTOR的磷酸化水平，但对海马区无明显影响。第7天，单次注射BDNF-原肌球蛋白受体激酶B激活剂7，8-二羟基黄酮经腹腔或鞘内注射。值得注意的是，只有鞘内注射改善了PWMT和TFL。此外，腹腔注射mTOR抑制剂雷帕霉素未能引起任何行为改变，而鞘内注射雷帕霉素则改善了CRS诱导的异常PWMT和TFL。综上所述，CRS可通过改变脊髓内BDNF-mTOR信号通路诱导异常的疼痛敏感性。(C)2019 IBRO。爱思唯尔有限公司出版。保留所有权利。
Stress is a non-specific, systemic, physiological response of the body to strong internal and external environmental stimuli. Accumulating evidence has suggested that stress, particularly chronic restraint stress (CRS), can reduce pain threshold and increase pain sensitivity. However, pathogenic and therapeutic mechanisms underlying CRS remain unclear. Here, we aimed to investigate roles of the brain-derived neurotrophic factor (BDNF)-mammalian target of rapamycin (mTOR) signaling pathway in CRS-induced abnormal pain sensitivity. CRS was successfully mimicked 7 days after model development, and paw withdrawal mechanical threshold (PWMT) and tail-flick latency (TFL) were evaluated. CRS significantly altered BDNF and mTOR phosphorylation in the anterior cingulate cortex and spinal cord but not in the hippocampus. On day 7, a single dose of 7,8-dihydroxyflavone, an activator of BDNF-tropomyosin receptor kinase B, was administered via intraperitoneal or intrathecal injection. Notably, only the intrathecal injection improved PWMT and TFL. Additionally, an intraperitoneal injection of rapamycin, an mTOR inhibitor, failed to induce any behavioral changes, whereas a single intrathecal injection of rapamycin improved abnormal CRS-induced PWMT and TFL. In conclusion, CRS can induce abnormal pain sensitivity, probably by altering the BDNF-mTOR signaling pathway in the spinal cord. (C) 2019 IBRO. Published by Elsevier Ltd. All rights reserved.