Genetic and functional evidence for gp130/IL6ST-induced transient receptor potential ankyrin 1 upregulation in uninjured but not injured neurons in a mouse model of neuropathic pain.
Genetic and functional evidence for gp130/IL6ST-induced transient receptor potential ankyrin 1 upregulation in uninjured but not injured neurons in a mouse model of neuropathic pain.
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DOI：
10.1097/j.pain.0000000000002402
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发表时间：
2022-03-01
期刊：
影响因子：
7.4
通讯作者：
Kress M
中科院分区：
文献类型：
--
作者：
Kalpachidou T;Malsch P;Qi Y;Mair N;Geley S;Quarta S;Kummer KK;Kress M
Gp130是神经损伤后机械超敏反应的重要调节因子。在未损伤但未损伤的神经元中，未损伤的神经损伤后瞬时受体电位Ankyrin 1反应性上调。Gp130上调未受损伤神经元中的瞬时受体潜在锚蛋白1，这与神经病理性疼痛的信号有关。周围神经损伤会导致背根神经节的显著改变，从而导致神经病理性疼痛的发展。尽管多模式机械敏感的瞬时受体潜在锚蛋白1(TRPA1)离子通道正在成为潜在止痛治疗的相关靶点，但临床前研究并未提供明确的机制洞察其与神经病理性疼痛发病机制的相关性。通过使用NAV1.8表达神经元中白介素6(IL-6)信号转导蛋白gp130有条件缺失的转基因小鼠模型(sNS-gp130−/−)，我们在备用神经损伤模型中提供了IL-6/gp130与TRPA1之间的机制调节联系。在体内的von Frey行为测试中，无髓鞘神经损伤小鼠的戒断阈值降低，而在体外皮肤神经记录中，无髓鞘伤害性初级传入的机械敏感性显著增加，表明幸免神经损伤小鼠表现出严重的机械过敏。与野生型和对照gp130fl/fl小鼠相比，sNS-gp130−/−小鼠在SNI后没有出现机械性超敏反应，感觉神经元中TRPA1mRNA的表达水平较低，而重组腺病毒gp130在体外可部分恢复其表达。重要的是，未损伤但未损伤的神经元对TRPA1激动剂肉桂醛的反应性增强，而SNSgp130−/−小鼠来源的神经元对肉桂醛的反应性显著降低。我们的研究首次表明，在SNI模型中，TRPA1的上调特异性地归因于未损伤的神经元，这依赖于IL-6信号转导蛋白gp130。我们提供了神经损伤后TRPA1调节之谜的解决方案，并强调其作为神经病理性疼痛障碍的重要靶点的重要性。
gp130 is a critically important regulator of mechanical hypersensitivity after nerve injury. Transient receptor potential ankyrin 1-responsiveness is upregulated after spared nerve injury in uninjured but not injured neurons. gp130 upregulates transient receptor potential ankyrin 1 in uninjured neurons, and this is associated with signatures of neuropathic pain. Peripheral nerve injuries result in pronounced alterations in dorsal root ganglia, which can lead to the development of neuropathic pain. Although the polymodal mechanosensitive transient receptor potential ankyrin 1 (TRPA1) ion channel is emerging as a relevant target for potential analgesic therapies, preclinical studies do not provide unequivocal mechanistic insight into its relevance for neuropathic pain pathogenesis. By using a transgenic mouse model with a conditional depletion of the interleukin-6 (IL-6) signal transducer gp130 in Nav1.8 expressing neurons (SNS-gp130−/−), we provide a mechanistic regulatory link between IL-6/gp130 and TRPA1 in the spared nerve injury (SNI) model. Spared nerve injury mice developed profound mechanical hypersensitivity as indicated by decreased withdrawal thresholds in the von Frey behavioral test in vivo, as well as a significant increase in mechanosensitivity of unmyelinated nociceptive primary afferents in ex vivo skin-nerve recordings. In contrast to wild type and control gp130fl/fl animals, SNS-gp130−/− mice did not develop mechanical hypersensitivity after SNI and exhibited low levels of Trpa1 mRNA in sensory neurons, which were partially restored by adenoviral gp130 re-expression in vitro. Importantly, uninjured but not injured neurons developed increased responsiveness to the TRPA1 agonist cinnamaldehyde, and neurons derived from SNS-gp130−/− mice after SNI were significantly less responsive to cinnamaldehyde. Our study shows for the first time that TRPA1 upregulation is attributed specifically to uninjured neurons in the SNI model, and this depended on the IL-6 signal transducer gp130. We provide a solution to the enigma of TRPA1 regulation after nerve injury and stress its significance as an important target for neuropathic pain disorders.
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