Microglia take on an altered morphology during chronic opioid treatment. This morphological change is broadly used to identify the activated microglial state associated with opioid side effects, including tolerance and opioid-induced hyperalgesia (OIH). Microglia display similar morphological responses in the spinal cord after peripheral nerve injury (PNI). Consistent with this observation, functional studies have suggested that microglia activated by opioids or PNI engage common molecular mechanisms to induce hypersensitivity. In this article, we conducted deep RNA sequencing (RNA-seq) and morphological analysis of spinal cord microglia in male mice to comprehensively interrogate transcriptional states and mechanistic commonality between multiple models of OIH and PNI. After PNI, we identify an early proliferative transcriptional event across models that precedes the upregulation of histological markers of microglial activation. However, we found no proliferative transcriptional response associated with opioid-induced microglial activation, consistent with histological data, indicating that the number of microglia remains stable during morphine treatment, whereas their morphological response differs from PNI models. Collectively, these results establish the diversity of pain-associated microglial transcriptomic responses and point towards the targeting of distinct insult-specific microglial responses to treat OIH, PNI, or other central nervous system pathologies.

中文翻译：

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阿片类药物暴露和神经性疼痛期间小胶质细胞转录反应的多样性。


小胶质细胞在慢性阿片类药物治疗期间发生形态改变。这种形态学变化广泛用于识别与阿片类药物副作用相关的活化小胶质细胞状态，包括耐受性和阿片类药物诱导的痛觉过敏 （OIH）。小胶质细胞在周围神经损伤 （PNI） 后脊髓中表现出相似的形态反应。与这一观察结果一致，功能研究表明，由阿片类药物或 PNI 激活的小胶质细胞参与诱导超敏反应的常见分子机制。在本文中，我们对雄性小鼠脊髓小胶质细胞进行了深度 RNA 测序 （RNA-seq） 和形态学分析，以全面询问 OIH 和 PNI 多个模型之间的转录状态和机制共性。在 PNI 之后，我们在模型中确定了在小胶质细胞活化的组织学标志物上调之前的早期增殖转录事件。然而，我们发现没有与阿片类药物诱导的小胶质细胞激活相关的增殖转录反应，这与组织学数据一致，表明小胶质细胞的数量在吗啡治疗期间保持稳定，而它们的形态学反应与 PNI 模型不同。总的来说，这些结果确定了与疼痛相关的小胶质细胞转录组反应的多样性，并指向靶向不同的损伤特异性小胶质细胞反应以治疗 OIH、PNI 或其他中枢神经系统病变。