Background

There are clinically relevant sex differences in acute and chronic pain mechanisms, but we are only beginning to understand their mechanistic basis. Transcriptome analyses of rodent whole dorsal root ganglion (DRG) have revealed sex differences, mostly in immune cells. We examined the transcriptome and translatome of the mouse DRG with the goal of identifying sex differences.

Methods

We used translating ribosome affinity purification sequencing and behavioral pharmacology to test the hypothesis that in Nav1.8-positive neurons, most of which are nociceptors, translatomes would differ by sex.

Results

We found 80 genes with sex differential expression in the whole DRG transcriptome and 66 genes whose messenger RNAs were sex differentially actively translated (translatome). We also identified different motifs in the 3′ untranslated region of messenger RNAs that were sex differentially translated. In further validation studies, we focused on Ptgds, which was increased in the translatome of female mice. The messenger RNA encodes the prostaglandin PGD₂ synthesizing enzyme. We observed increased PTGDS protein and PGD₂ in female mouse DRG. The PTGDS inhibitor AT-56 caused intense pain behaviors in male mice but was only effective at high doses in female mice. Conversely, female mice responded more robustly to another major prostaglandin, PGE₂, than did male mice. PTGDS protein expression was also higher in female cortical neurons, suggesting that DRG findings may be generalizable to other nervous system structures.

Conclusions

Our results demonstrate sex differences in nociceptor-enriched translatomes and reveal unexpected sex differences in one of the oldest known nociceptive signaling molecule families, the prostaglandins.

中文翻译：

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伤害感受器翻译组的性别差异导致雄性和雌性小鼠前列腺素信号转导的差异

背景

急性和慢性疼痛机制在临床上存在相关的性别差异，但我们才刚刚开始了解它们的机制基础。啮齿动物整个背根神经节 (DRG) 的转录组分析揭示了性别差异，主要存在于免疫细胞中。我们检查了小鼠 DRG 的转录组和翻译组，目的是识别性别差异。

方法

我们使用翻译核糖体亲和纯化测序和行为药理学来检验假设，即在 Nav1.8 阳性神经元（其中大部分是伤害感受器）中，翻译体会因性别而异。

结果

我们在整个 DRG 转录组中发现了 80 个具有性别差异表达的基因和 66 个其信使 RNA 是性别差异主动翻译（翻译组）的基因。我们还在信使 RNA 的 3' 非翻译区发现了不同的基序，这些基序是性别差异翻译的。在进一步的验证研究中，我们专注于Ptgds，它在雌性小鼠的翻译组中有所增加。信使 RNA 编码前列腺素 PGD ₂合成酶。我们观察到雌性小鼠 DRG 中PTGDS 蛋白和 PGD _2增加。PTGDS 抑制剂 AT-56 在雄性小鼠中引起剧烈疼痛行为，但仅在高剂量时对雌性小鼠有效。相反，雌性小鼠对另一种主要前列腺素 PGE _{2的反应更为强烈}, 而不是雄性小鼠。PTGDS 蛋白表达在女性皮层神经元中也更高，这表明 DRG 的发现可能适用于其他神经系统结构。

结论

我们的结果证明了富含伤害感受器的翻译组的性别差异，并揭示了已知最古老的伤害信号分子家族之一前列腺素的意外性别差异。