Extracellular signal‐regulated kinases 2 (Erk2) and Erk5 in the central nervous system differentially contribute to central sensitization in male mice
Extracellular signal‐regulated kinases 2 (Erk2) and Erk5 in the central nervous system differentially contribute to central sensitization in male mice
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DOI：
10.1002/jnr.24827
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发表时间：
2021-03
影响因子：
4.2
通讯作者：
F. Matsuura;Y. Satoh;Sayako Itakura;Toru Morohashi;M. Kawaguchi;Tetsuya Takahashi;Koji Iwanaga;Hayato Terashima;Yasushi Kobayashi;Xin Wang;T. Ishizuka;S. Endo;Takehiko Ikeda
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作者：
F. Matsuura;Y. Satoh;Sayako Itakura;Toru Morohashi;M. Kawaguchi;Tetsuya Takahashi;Koji Iwanaga;Hayato Terashima;Yasushi Kobayashi;Xin Wang;T. Ishizuka;S. Endo;Takehiko Ikeda
在某些情况下，例如炎症和神经损伤，神经系统对传入的伤害性刺激变得格外敏感。疼痛过敏如何发生是该领域的关键问题，因为它最终导致慢性疼痛。中枢敏化代表由于中枢神经系统（CNS）内神经信号的增加而增强的疼痛敏感性。特别是，大量证据表明中枢敏化的潜在机制与脊髓神经元的变化有关。细胞外信号调节激酶作为中枢敏化的关键分子而受到关注。此前，我们使用中枢神经系统中 Cre-loxP 介导的 Erk2 缺失小鼠，揭示了脊髓神经元中细胞外信号调节激酶 2 (Erk2) 的异构体特异性功能，以实现中枢敏化。尽管如此，脊髓神经元中的细胞外信号调节激酶 5 (Erk5) 如何促进中枢敏化尚未得到直接测试，Erk5 和 Erk2 的功能相关性也不清楚。在这里，我们表明中枢神经系统中的 Erk5 和 Erk2 在中枢敏化中发挥冗余和/或不同的作用，具体取决于可塑性环境（细胞类型、疼痛类型、时间等）。我们使用中枢神经系统中 Erk5 缺失的雄性小鼠，发现 Erk5 在福尔马林诱导的炎症疼痛模型中的中枢敏化中发挥重要作用。与单独删除任一同工型相比，同时删除 Erk2 和 Erk5 会导致该模型中中枢敏化的更大减弱。相反，Erk2 而不是 Erk5 在神经性疼痛（一种由神经损伤引起的慢性疼痛）的中枢敏化中发挥重要作用。我们的结果表明 Erk 信号传导在中枢敏化中的复杂机制。
Nervous systems are designed to become extra sensitive to afferent nociceptive stimuli under certain circumstances such as inflammation and nerve injury. How pain hypersensitivity comes about is key issue in the field since it ultimately results in chronic pain. Central sensitization represents enhanced pain sensitivity due to increased neural signaling within the central nervous system (CNS). Particularly, much evidence indicates that underlying mechanism of central sensitization is associated with the change of spinal neurons. Extracellular signal‐regulated kinases have received attention as key molecules in central sensitization. Previously, we revealed the isoform‐specific function of extracellular signal‐regulated kinase 2 (Erk2) in spinal neurons for central sensitization using mice with Cre‐loxP‐mediated deletion of Erk2 in the CNS. Still, how extracellular signal‐regulated kinase 5 (Erk5) in spinal neurons contributes to central sensitization has not been directly tested, nor is the functional relevance of Erk5 and Erk2 known. Here, we show that Erk5 and Erk2 in the CNS play redundant and/or distinct roles in central sensitization, depending on the plasticity context (cell types, pain types, time, etc.). We used male mice with Erk5 deletion specifically in the CNS and found that Erk5 plays important roles in central sensitization in a formalin‐induced inflammatory pain model. Deletion of both Erk2 and Erk5 leads to greater attenuation of central sensitization in this model, compared to deletion of either isoform alone. Conversely, Erk2 but not Erk5 plays important roles in central sensitization in neuropathic pain, a type of chronic pain caused by nerve damage. Our results suggest the elaborate mechanisms of Erk signaling in central sensitization.