Ghazisaeidi Shahrzad, Muley Milind M, Tu YuShan, Finn David P, Kolahdouzan Mahshad, Pitcher Graham M, Kim Doyeon, Sengar Ameet S, Ramani Arun K, Brudno Michael, Salter Michael W
Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
Program in Neuroscience & Mental Health, The Hospital for Sick Children, Toronto, Ontario, Canada.
Br J Pharmacol. 2023 Nov;180(21):2822-2836. doi: 10.1111/bph.16168. Epub 2023 Jul 27.
Chronic pain is a devastating problem affecting one in five individuals around the globe, with neuropathic pain the most debilitating and poorly treated type of chronic pain. Advances in transcriptomics have contributed to cataloguing diverse cellular pathways and transcriptomic alterations in response to peripheral nerve injury but have focused on phenomenology and classifying transcriptomic responses.
To identifying new types of pain-relieving agents, we compared transcriptional reprogramming changes in the dorsal spinal cord after peripheral nerve injury cross-sex and cross-species, and imputed commonalities, as well as differences in cellular pathways and gene regulation.
We identified 93 transcripts in the dorsal horn that were increased by peripheral nerve injury in male and female mice and rats. Following gene ontology and transcription factor analyses, we constructed a pain interactome for the proteins encoded by the differentially expressed genes, discovering new, conserved signalling nodes. We investigated the interactome with the Drug-Gene database to predict FDA-approved medications that may modulate key nodes within the network. The top hit from the analysis was fostamatinib, the molecular target of which is the non-receptor spleen associated tyrosine kinase (Syk), which our analysis had identified as a key node in the interactome. We found that intrathecally administrating the active metabolite of fostamatinib, R406 and another Syk inhibitor P505-15, significantly reversed pain hypersensitivity in both sexes.
Thus, we have identified and shown the efficacy of an agent that could not have been previously predicted to have analgesic properties.
慢性疼痛是一个极具破坏性的问题，全球五分之一的人受其影响，其中神经性疼痛是最使人衰弱且治疗效果不佳的慢性疼痛类型。转录组学的进展有助于梳理各种细胞通路以及外周神经损伤后转录组的变化，但主要集中在现象学和转录组反应的分类上。
为了确定新型止痛剂，我们比较了外周神经损伤后脊髓背角跨性别和跨物种的转录重编程变化，并推断细胞通路和基因调控的共性及差异。
我们在背角中鉴定出93种转录本，雄性和雌性小鼠及大鼠的外周神经损伤会使其增加。经过基因本体论和转录因子分析后，我们构建了由差异表达基因编码的蛋白质的疼痛相互作用组，发现了新的保守信号节点。我们用药物-基因数据库研究该相互作用组，以预测可能调节网络中关键节点的美国食品药品监督管理局（FDA）批准的药物。分析中排名第一的是福斯替尼，其分子靶点是非受体脾相关酪氨酸激酶（Syk），我们的分析已将其确定为相互作用组中的一个关键节点。我们发现，鞘内注射福斯替尼的活性代谢物R406和另一种Syk抑制剂P505-15，可显著逆转两性的疼痛超敏反应。
因此，我们已经确定并证明了一种以前无法预测具有镇痛特性的药物的疗效。
