Hedgehog signaling plays a crucial role in hyperalgesia associated with neuropathic pain in mice
Hedgehog signaling plays a crucial role in hyperalgesia associated with neuropathic pain in mice
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DOI：
10.1111/jnc.15613
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发表时间：
2022-04
影响因子：
4.7
通讯作者：
Hiroaki Okuda;T. Ishikawa;Kiyomi Hori;Nichakarn Kwankaew;N. Ozaki
中科院分区：
文献类型：
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作者：
Hiroaki Okuda;T. Ishikawa;Kiyomi Hori;Nichakarn Kwankaew;N. Ozaki
神经病理性疼痛是由神经损伤引起的神经系统衰弱性慢性综合征。在果蝇中，Hedgehog（Hh）信号通路与增加的疼痛敏感性（痛觉过敏）有关，但不影响基线伤害性阈值。一般来说，Hh信号通路对脊椎动物神经性疼痛的贡献是一个高度争论的问题。另外，我们研究了Hh信号在机械异常性疼痛中的潜在作用，使用神经性疼痛的小鼠模型。脊髓神经横断（SNT）手术后7天，与假手术组相比，同侧脊髓背角的小胶质细胞活化增加;然而，手术后21天，小胶质细胞活化减少。相比之下，脊髓中的星形胶质细胞活化在两组之间没有差异。在术后第21天，SNT组在外周神经胶质细胞中的音刺猬表达显著上调，但在背根神经节（DRG）神经元中没有。鞘内施用Hh信号传导抑制剂维莫德吉减弱了术后第21天观察到的机械性异常性疼痛。相反，鞘内治疗与Hh信号激活剂smoothened激动剂在幼稚小鼠诱导机械异常性疼痛，这是由ATP转运抑制剂氯膦酸盐废除。此外，通过用维莫德吉预处理抑制Hh信号传导显著降低培养的DRG细胞中ATP分泌和细胞内钙离子水平自发升高的频率/数量。因此，Hh信号通路似乎通过ATP释放调节DRG神经元的神经活性，并且其在神经病理性疼痛的小鼠模型中在维持机械性异常性疼痛和超敏性中起重要作用。
Neuropathic pain is a debilitating chronic syndrome of the nervous system caused by nerve injury. In Drosophila, the Hedgehog (Hh) signaling pathway is related to increased pain sensitivity (hyperalgesia) but does not affect the baseline nociceptive threshold. In general, the contribution of the Hh signaling pathway to neuropathic pain in vertebrates is a highly debated issue. Alternatively, we investigated the potential role of Hh signaling in mechanical allodynia using a mouse model of neuropathic pain. Seven days after spinal nerve‐transection (SNT) surgery, microglial activation increased in the ipsilateral spinal dorsal horn compared with that in the sham group; however, 21 days after surgery, microglial activation decreased. Contrastingly, astrocyte activation in the spinal cord did not differ between the groups. On day 21 of postsurgery, the SNT group showed marked upregulation of sonic hedgehog expression in peripheral glial cells but not in dorsal root ganglion (DRG) neurons. Intrathecal administration of the Hh signaling inhibitor vismodegib attenuated the mechanical allodynia observed on day 21 postsurgery. Conversely, intrathecal treatment with the Hh signaling activator smoothened agonist in naive mice induced mechanical allodynia, which was abolished by the ATP transporter inhibitor clodronate. Moreover, inhibition of Hh signaling by pretreatment with vismodegib significantly reduced ATP secretion and the frequency/number of spontaneous elevations of intracellular calcium ion levels in cultured DRG cells. Thus, the Hh signaling pathway appears to modulate the neural activity of DRG neurons via ATP release, and it plays an important role in sustaining mechanical allodynia and hypersensitivity in a mouse model of neuropathic pain.