Spinal translocator protein alleviates chronic neuropathic pain behavior and modulates spinal astrocyte-neuronal function in rats with L5 spinal nerve ligation model
Spinal translocator protein alleviates chronic neuropathic pain behavior and modulates spinal astrocyte-neuronal function in rats with L5 spinal nerve ligation model
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DOI：
10.1097/j.pain.0000000000000339
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发表时间：
2016-01-01
期刊：
影响因子：
7.4
通讯作者：
Jin, Yi
中科院分区：
文献类型：
--
作者：
Liu, Xiaoming;Liu, Hongjun;Jin, Yi
近年来研究发现，转运蛋白（TSPO）在炎症性疼痛和神经病理性疼痛等多种神经系统疾病中发挥重要作用。然而，确切的机制仍不清楚。本研究在大鼠L5脊神经结扎（SNL）模型上探讨脊髓TSPO的分布及其抗慢性神经病理性疼痛（CNP）的可能机制。我们的研究结果表明，TSPO在SNL后脊髓背角以时间相关的方式上调。脊髓TSPO主要在星形胶质细胞中表达。单次鞘内注射TSPO激动剂Ro 5 -4864，而不是TSPO拮抗剂PK 11195，以剂量依赖性方式减轻机械异常性疼痛。单次椎管内注射TSPO过表达慢病毒（LV-TSPO），但不是TSPO抑制慢病毒（LV-shTSPO），也缓解了CNP的发展。与对照组相比，在第3天鞘内施用2 μ g Ro 5 -4864在早期阶段（第5-7天）诱导TSPO蛋白含量显著增加，而在慢性期（第14-21天）抑制TSPO活化。Ro 5 -4864抑制星形胶质细胞和p-JNK 1活化，并在体内和体外研究中降低CXCL 1表达。Ro 5 -4864还减弱脊髓CXCR 2和p-ERK表达。这些结果表明，早期上调TSPO可以引起对CNP的有效镇痛作用，这可能部分归因于抑制CXCL 1-CXCR 2依赖的星形胶质细胞-神经元信号传导和中枢敏化。TSPO信号通路可能为CNP的治疗提供新的策略。
Recent studies reported the translocator protein (TSPO) to play critical roles in several kinds of neurological diseases including the inflammatory and neuropathic pain. However, the precise mechanism remains unclear. This study was undertaken to explore the distribution and possible mechanism of spinal TSPO against chronic neuropathic pain (CNP) in a rat model of L5 spinal nerve ligation (SNL). Our results showed that TSPO was upregulated in a time-related manner in the spinal dorsal horn after SNL. Spinal TSPO was predominately expressed in astrocytes. A single intrathecal injection of TSPO agonist Ro5-4864, but not TSPO antagonist PK11195, alleviated the mechanical allodynia in a dose-dependent manner. A single intraspinal injection of TSPO overexpression lentivirus (LV-TSPO), but not TSPO inhibited lentivirus (LV-shTSPO), also relieved the development of CNP. Intrathecal administration of 2 mu g Ro5-4864 on day 3 induced a significant increase of TSPO protein content at the early stage (days 5-7) while inhibited the TSPO activation during the chronic period (days 14-21) compared with the control group. Ro5-4864 suppressed the astrocytes and p-JNK1 activation and decreased the CXCL1 expression in both in vivo and in vitro studies. Ro5-4864 also attenuated the spinal CXCR2 and p-ERK expressions. These results suggested that early upregulation of TSPO could elicit potent analgesic effects against CNP, which might be partly attributed to the inhibition of CXCL1-CXCR2-dependent astrocyte-to-neuron signaling and central sensitization. TSPO signaling pathway may present a novel strategy for the treatment of CNP.