Sankaranarayanan Ishwarya, Kume Moeno, Mohammed Ayaan, Mwirigi Juliet M, Inturi Nikhil Nageswar, Munro Gordon, Petersen Kenneth A, Tavares-Ferreira Diana, Price Theodore J
Department of Neuroscience, Center for Advanced Pain Studies, School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, TX.
Hoba Therapeutics ApS, Copenhagen, Denmark.
Pain. 2025 Jun 1;166(6):1395-1405. doi: 10.1097/j.pain.0000000000003523. Epub 2025 Jan 28.
Hyperalgesic priming is a model system that has been widely used to understand plasticity in painful stimulus-detecting sensory neurons, called nociceptors. A key feature of this model system is that following priming, stimuli that do not normally cause hyperalgesia now readily provoke this state. We hypothesized that hyperalgesic priming occurs because of reorganization of translation of mRNA in nociceptors. To test this hypothesis, we used paclitaxel treatment as the priming stimulus and translating ribosome affinity purification to measure persistent changes in mRNA translation in Na v 1.8+ nociceptors. Translating ribosome affinity purification sequencing revealed 161 genes with persistently altered mRNA translation in the primed state. Among these genes, we identified Gpr88 as upregulated and Metrn as downregulated. To provide functional evidence for these changes in hyperalgesic priming in a related priming model, we used the interleukin-6 priming model. A GPR88 agonist injection into the paw had no effect in naive mice but caused mechanical hypersensitivity and grimacing responses in female primed mice. Systemic Meteorin treatment in primed mice completely reversed established hyperalgesic priming mechanical hypersensitivity and grimacing responses to prostaglandin E2 in female mice. Our work demonstrates that altered nociceptor translatomes are causative in producing hyperalgesic priming in multiple models in female mice.
痛觉过敏启动是一种模型系统，已被广泛用于理解检测疼痛刺激的感觉神经元（即伤害感受器）中的可塑性。该模型系统的一个关键特征是，在启动后，通常不会引起痛觉过敏的刺激现在很容易引发这种状态。我们假设痛觉过敏启动的发生是由于伤害感受器中mRNA翻译的重新组织。为了验证这一假设，我们使用紫杉醇治疗作为启动刺激，并采用翻译核糖体亲和纯化技术来测量Nav 1.8+伤害感受器中mRNA翻译的持续变化。翻译核糖体亲和纯化测序揭示了161个在启动状态下mRNA翻译持续改变的基因。在这些基因中，我们鉴定出Gpr88上调，Metrn下调。为了在相关启动模型中为痛觉过敏启动的这些变化提供功能证据，我们使用了白细胞介素-6启动模型。向爪部注射GPR88激动剂对未致敏小鼠没有影响，但在雌性启动小鼠中引起机械性超敏反应和痛苦表情反应。对启动小鼠进行全身Metrn治疗完全逆转了已建立的痛觉过敏启动的机械性超敏反应以及雌性小鼠对前列腺素E2的痛苦表情反应。我们的研究表明，伤害感受器翻译组的改变在雌性小鼠的多个模型中导致了痛觉过敏启动。
