Upregulation of tumor necrosis factor-alpha in the anterior cingulate cortex contributes to neuropathic pain and pain-associated aversion
Upregulation of tumor necrosis factor-alpha in the anterior cingulate cortex contributes to neuropathic pain and pain-associated aversion
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前扣带皮层肿瘤坏死因子-α 的上调会导致神经性疼痛和与疼痛相关的厌恶。
DOI：
10.1016/j.nbd.2019.04.012
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发表时间：
2019-10-01
影响因子：
6.1
通讯作者：
Zang, Ying
中科院分区：
文献类型：
--
作者：
Yao, Pei-Wen;Wang, Shao-Kun;Zang, Ying
与损伤相关的疼痛涉及主观感知和情感体验。前扣带皮层（ACC）是参与疼痛处理情感成分的关键区域。然而，周围神经损伤后ACC兴奋性增强背后的神经免疫机制仍未完全明晰。我们之前的研究表明，肿瘤坏死因子-α（TNF-α）过表达会导致脊髓中周围传入神经的过度兴奋以及突触传递增强。在此，我们旨在揭示ACC中TNF-α在ACC过度兴奋和神经性疼痛中可能发挥的作用。c-Fos是一种广泛应用的神经元活动标志物，在神经性疼痛发展的早期[术后（PO）1小时]及后期（PO第7天和第10天），尤其在对侧ACC中被诱导表达。 spared nerve injury（SNI， spared nerve injury，坐骨神经分支选择性损伤）从PO第5天到第14天会使对侧ACC中的TNF-α水平升高，这相对于从PO第1天到第14天明显降低的同侧爪缩阈值而言有所延迟。将抗TNF-α抗体微量注射到ACC中，完全消除了c-Fos的过表达，并极大地减轻了SNI诱导的疼痛厌恶和机械性异常性疼痛，这表明ACC中的TNF-α在疼痛厌恶和疼痛维持中起着重要作用。此外，通过Gi偶联的人M4毒蕈碱受体（hM4Di）或Gq偶联的人M3毒蕈碱受体（hM3Dq，一种仅由设计药物激活的设计受体，DREADD）调节ACC锥体神经元，会显著改变ACC中TNF-α的水平以及机械性爪缩阈值。TNF-α与ACC神经元之间的正向相互作用可能会调节细胞因子微环境，从而导致神经性疼痛。
Injury associated pain involves subjective perception and emotional experience. The anterior cingulate cortex (ACC) is a key area involved in the affective component of pain processing. However, the neuroimmune mechanisms underlying enhanced ACC excitability following peripheral nerve injury are still not fully understood. Our previous work has shown that tumor necrosis factor-alpha (TNF-alpha) overexpression leads to peripheral afferent hyperexcitability and synaptic transmission potentiation in spinal cord. Here, we aimed to reveal the potential role of ACC TNF-alpha in ACC hyperexcitability and neuropathic pain. c-Fos, a widely used neuronal activity marker, was induced especially in contralateral ACC early [postoperative (PO) 1 h] and later (PO day 7 and 10) during the development of neuropathic pain. Spared nerve injury (SNI) elevated TNF-alpha level in contralateral ACC from PO day 5 to 14, delayed relative to decreased ipsilateral paw withdrawal threshold apparent from PO day 1 to 14. Microinjection of anti-TNF-alpha antibody into the ACC completely eliminated c-Fos over expression and greatly attenuated pain aversion and mechanical allodynia induced by SNI, suggesting an important role of ACC TNF-alpha in the pain aversiveness and pain maintenance. Furthermore, modulating ACC pyramidal neurons via a Gi-coupled human M4 muscarinic receptor (hM4Di) or a Gq-coupled human M3 muscarinic receptor (hM3Dq), a type of designer receptors exclusively activated by designer drugs (DREADD), greatly changed the ACC TNF-alpha level and the mechanical paw withdrawal threshold. The positive interactions between TNF-alpha and ACC neurons might modulate the cytokine microenvironment thus contribute to the neuropathic pain.