Distinct microglial transcriptional responses during opioid exposure or neuropathic pain [rat]

In settings of heightened pain sensitivity, such as following peripheral nerve injury (PNI) or opioid-induced hyperalgesia (OIH), microglia take on an activated phenotype. Functional studies have suggested that microglia activated by PNI or chronic opioids then engage common mechanisms to facilitate pain. Here we conducted RNA sequencing of acutely isolated spinal cord microglia to comprehensively interrogate commonality between PNI and OIH. By combining our results with meta-analysis of published datasets, we identify transcriptional signatures of microglial reactivity that differ between PNI models over time, opioid exposure, or CNS pathology, despite similar histological outcomes. Collectively, these results reveal a discrepancy between histological markers of activation and transcriptional response, and provide a resource of pain-associated microglial transcriptomes that caution against a universal signature of microglia activation.在痛觉敏感性升高的情境下，如外周神经损伤（peripheral nerve injury, PNI）或阿片类药物诱导的痛觉过敏（opioid-induced hyperalgesia, OIH）发生后，小胶质细胞会呈现激活表型。已有功能研究表明，经PNI或慢性阿片类药物激活的小胶质细胞，可通过共同的分子机制促进疼痛的发生与维持。本研究对急性分离的脊髓小胶质细胞进行RNA测序，以全面解析PNI与OIH之间的分子共性。本研究将测序结果与已发表数据集的荟萃分析相结合，鉴定出小胶质细胞激活反应的转录特征：尽管不同模型的组织学结局相似，但这些特征会随PNI模型的时间进程、阿片类药物暴露情况或中枢神经系统（central nervous system, CNS）病理状态的差异而发生改变。综上，本研究结果揭示了小胶质细胞激活的组织学标志物与转录应答之间的不一致性，并构建了疼痛相关小胶质细胞转录组资源，提醒学界不应将单一特征作为小胶质细胞激活的通用判断标准。