Uttam Sonali, Wong Calvin, Amorim Inês S, Jafarnejad Seyed Mehdi, Tansley Shannon N, Yang Jieyi, Prager-Khoutorsky Masha, Mogil Jeffrey S, Gkogkas Christos G, Khoutorsky Arkady
Department of Anesthesia, McGill University, Montreal, QC H3A 0G1, Canada.
Patrick Wild Centre and Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh EH8 9XD, UK.
Neurobiol Pain. 2018 Aug-Dec;4:35-44. doi: 10.1016/j.ynpai.2018.04.001. Epub 2018 Apr 18.
Acute pain serves as a protective mechanism, guiding the organism away from actual or potential tissue injury. In contrast, chronic pain is a debilitating condition without any obvious physiological function. The transition to, and the maintenance of chronic pain require new gene expression to support biochemical and structural changes within the pain pathway. The regulation of gene expression at the level of mRNA translation has emerged as an important step in the control of protein expression in the cell. Recent studies show that signaling pathways upstream of mRNA translation, such as mTORC1 and ERK, are upregulated in chronic pain conditions, and their inhibition effectively alleviates pain in several animal models. Despite this progress, mRNAs whose translation is altered in chronic pain conditions remain largely unknown. Here, we performed genome-wide translational profiling of dorsal root ganglion (DRG) and spinal cord dorsal horn tissues in a mouse model of neuropathic pain, spared nerve injury (SNI), using the ribosome profiling technique. We identified distinct subsets of mRNAs that are differentially translated in response to nerve injury in both tissues. We discovered key converging upstream regulators and pathways linked to mRNA translational control and neuropathic pain. Our data are crucial for the understanding of mechanisms by which mRNA translation promotes persistent hypersensitivity after nerve injury.
急性疼痛作为一种保护机制，引导机体远离实际的或潜在的组织损伤。相比之下，慢性疼痛是一种使人衰弱的病症，没有任何明显的生理功能。向慢性疼痛的转变以及慢性疼痛的维持需要新的基因表达来支持疼痛通路内的生化和结构变化。在mRNA翻译水平上对基因表达的调控已成为细胞中蛋白质表达控制的重要一步。最近的研究表明，mRNA翻译上游的信号通路，如mTORC1和ERK，在慢性疼痛状态下上调，并且它们的抑制在几种动物模型中有效减轻了疼痛。尽管取得了这一进展，但在慢性疼痛状态下其翻译发生改变的mRNA在很大程度上仍然未知。在这里，我们使用核糖体分析技术，在神经性疼痛小鼠模型 spared nerve injury (SNI) 中，对背根神经节 (DRG) 和脊髓背角组织进行了全基因组翻译分析。我们鉴定出在两种组织中响应神经损伤而差异翻译的不同mRNA亚群。我们发现了与mRNA翻译控制和神经性疼痛相关的关键汇聚上游调节因子和通路。我们的数据对于理解mRNA翻译促进神经损伤后持续超敏反应的机制至关重要。
