Mountadem Sarah, Herault Karine, Peirs Cedric, da Silva Borges Gisela, Voisin Daniel L, Antri Myriam, Dallel Radhouane
Université Clermont Auvergne, CHU Clermont-Ferrand, Inserm, Neuro-Dol, Clermont-Ferrand F-63000, France.
Univ. de Bordeaux, Inserm, Neurocentre Magendie, Bordeaux F-33000, France.
Brain. 2025 Aug 1;148(8):2951-2964. doi: 10.1093/brain/awaf122.
Chronic facial pain, a frequent and disabling condition, is maintained by central sensitization, which results in pain hypersensitivity. Although it is well established that reactive astrocytes play a key role in persistent pain mechanisms, the role of disruption of the normal capacity of astrocytes to maintain neuronal homeostasis is much less known. Here we show that persistent facial inflammation disturbs potassium homeostasis in the medullary dorsal horn of male rats, due to a sex-specific, drastic downregulation of astroglial inward rectifier potassium Kir4.1 channels. Using selective genetic tools, we establish that such downregulation, likely due to the release of IL-1β during inflammatory processing, is sufficient and required to drive pain hypersensitivity through altered K+ baseline levels. We further show that this chain of events can be prevented by selective upregulation of astroglial Kir4.1, or through systemic administration of 5-azacytidine, a DNA methylation modulator. Our results thus reveal a critical mechanism by which astrocyte dysfunction drives persistent inflammatory facial pain in males and discover the therapeutic potential of targeting central Kir4.1 for treating this disease.
慢性面部疼痛是一种常见的致残性疾病，由中枢敏化维持，可导致疼痛超敏反应。尽管已有充分证据表明反应性星形胶质细胞在持续性疼痛机制中起关键作用，但星形胶质细胞维持神经元内环境稳定的正常能力遭到破坏所起的作用却鲜为人知。在此，我们表明，持续性面部炎症会扰乱雄性大鼠延髓背角的钾离子稳态，这是由于星形胶质细胞内向整流钾离子通道Kir4.1出现性别特异性的显著下调所致。利用选择性基因工具，我们证实，这种下调可能是由于炎症过程中白细胞介素-1β的释放，它足以且必需通过改变钾离子基线水平来驱动疼痛超敏反应。我们进一步表明，这一系列事件可通过选择性上调星形胶质细胞的Kir4.1或通过全身给予DNA甲基化调节剂5-氮杂胞苷来预防。因此，我们的研究结果揭示了星形胶质细胞功能障碍导致雄性大鼠持续性炎症性面部疼痛的关键机制，并发现了靶向中枢Kir4.1治疗该疾病的潜在疗法。
