Know Thy Enemy: Untangling the Mysteries of Neuropathic Pain.
Know Thy Enemy: Untangling the Mysteries of Neuropathic Pain.
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了解你的敌人：解开神经性疼痛的谜团。
DOI：
10.1007/s12264-021-00748-y
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发表时间：
2021
影响因子：
5.6
通讯作者：
Duan,Bo
中科院分区：
文献类型：
--
作者：
Fatima,Mahar;Hor,ChiaChun;Duan,Bo
急性疼痛作为身体的警告系统起着重要的生理作用。然而，在许多患者中，神经损伤会导致神经性疼痛，这种疼痛可能持续多年，并扰乱他们的生活质量。不幸的是，神经性疼痛的机制仍然在很大程度上是未知的，这种情况在很大程度上是抵抗可用的治疗。开发治疗神经性疼痛的新策略取决于更好地理解从急性疼痛状态向慢性疼痛状态转变的分子，细胞和电路机制，这不仅涉及脊髓和大脑内的变化，还涉及疼痛初级感觉神经元的起始部位。新出现的实验证据表明，周围神经病变后转录谱的扰动可能有助于神经性疼痛的病理生理学[1-3]。尽管这些研究提供了对轴突切断诱导的转录组重构的见解，但它们在定义感觉神经元的多样性和异质性亚类方面的能力有限，这些感觉神经元以受干扰的转录组对神经损伤做出反应并有助于神经病理性疼痛的病理生理学。基于转录组的分类学已成为在正常条件下和发育期间鉴定背根神经节（DRG）中初级感觉神经元的异质子集的有效工具[4-7]。Wang等近期发表在Cell Research上的研究应用单细胞RNA测序技术，研究了神经病理性疼痛进展过程中腰背根节神经元分子和细胞成分的变化[8]，该研究在正常条件下鉴定了腰背根节中的16个神经元簇：6个肽能神经元簇（C1-1，C1-2和C2的4个亚簇），5个非肽能神经元簇（C3，C4的2个亚簇和C5的2个亚簇），和5个有髓鞘神经元类型簇（C7，C8和C9的3个亚簇）。然后，作者研究了备用神经损伤（SNI）后神经病理性疼痛进展过程中DRG神经元的基因表达谱。在正常条件下出现的所有16个簇在所有时间点都被识别。有趣的是，神经损伤导致出现3个额外的SNI诱导的神经元簇（SNIIC），它们具有相同的特征-转录因子（TF）Atf 3的强表达，Atf 3是ATF（激活TF）/CREB（cAMP反应元件结合蛋白）家族的成员，这与最近发现Atf 3作为转录重编程器在神经损伤后上调一致[9]。SNIIC 1和SNIIC 3神经元的数量在SNI后2天达到最大，并持续长达4周，而SNIIC 2在SNI后24 h短暂出现。轨迹研究显示，SNIIC 2神经元起源于Mrgprd+非肽能簇C5。SNIIC 2和Cldn 9 +/Gal+肽能簇C1-1从SNI后第2天开始转变为SNIIC 1。相比之下，SNIIC 3起源于Trappc 31+有髓鞘簇C8。
Acute pain plays an important physiological role as a warning system for the body. However, in many patients, nerve damage leads to neuropathic pain that can last for years and disrupts their quality of life. Unfortunately, neuropathic pain mechanisms remain largely unknown and this condition is largely resistant to available treatments. Developing new strategies to treat neuropathic pain depends on a better understanding of the molecular, cellular, and circuit mechanisms underlying the transition from the acute to the chronic pain state, which involves changes not only within the spinal cord and the brain, but also the initiation site of pain—primary sensory neurons. Emerging experimental evidence has shown perturbed transcriptional profiles following peripheral neuropathy that might contribute to the pathophysiology of neuropathic pain [1–3]. Alhough these studies provide insights into axotomy-induced transcriptome remodeling, they have a limited ability to define the diverse and heterogeneous subclasses of sensory neurons that respond with perturbed transcriptomes to nerve damage and contribute to the pathophysiology of neuropathic pain. Transcriptome-based taxonomy has emerged as an effective tool for identifying heterogeneous subsets of primary sensory neurons in the dorsal root ganglia (DRG) under normal conditions and during development [4–7]. In a recent study published in Cell Research, Wang et al. applied single-cell RNA sequencing technology to investigate changes in the molecular and cellular components of lumbar DRG neurons during the progression of neuropathic pain [8].In this study, 16 neuron clusters in the lumbar DRG were identified under normal conditions: 6 clusters of peptidergic neurons (C1-1, 4 sub-clusters of C1-2 and C2), 5 clusters of non-peptidergic neurons (C3, 2 sub-clusters of C4 and 2 sub-clusters of C5), and 5 clusters of myelinated neuron types (C7, 3 sub-clusters of C8 and C9). Then the authors examined gene expression profiles in DRG neurons during the progression of neuropathic pain following spared nerve injury (SNI). All 16 clusters that appeared under normal conditions were recognized at all time points. Interestingly, nerve injury resulted in the emergence of 3 additional SNI-induced neuronal clusters (SNIICs), which shared the same feature—strong expression of the transcription factor (TF) Atf3, a member of the ATF (activating TFs)/CREB (cAMP response element binding protein) family, consistent with a recent finding that Atf3 acts as a transcriptional reprogrammer that is upregulated following nerve injury [9]. The number of SNIIC1 and SNIIC3 neurons was maximal 2 days after SNI and persisted for as long as 4 weeks, while SNIIC2 was transiently present at 24 h after SNI. Trajectory investigation showed that SNIIC2 neurons originated from Mrgprd+ non-peptidergic cluster C5. Then SNIIC2 and Cldn9+/Gal+ peptidergic cluster C1-1 switched to SNIIC1 from day 2 after SNI. By contrast, SNIIC3 originated from Trappc3l+ myelinated cluster C8.