Kim Sun Kwang, Hayashi Hideaki, Ishikawa Tatsuya, Shibata Keisuke, Shigetomi Eiji, Shinozaki Youichi, Inada Hiroyuki, Roh Seung Eon, Kim Sang Jeong, Lee Gihyun, Bae Hyunsu, Moorhouse Andrew J, Mikoshiba Katsuhiko, Fukazawa Yugo, Koizumi Schuichi, Nabekura Junichi
J Clin Invest. 2016 May 2;126(5):1983-97. doi: 10.1172/JCI82859. Epub 2016 Apr 11.
Long-term treatments to ameliorate peripheral neuropathic pain that includes mechanical allodynia are limited. While glial activation and altered nociceptive transmission within the spinal cord are associated with the pathogenesis of mechanical allodynia, changes in cortical circuits also accompany peripheral nerve injury and may represent additional therapeutic targets. Dendritic spine plasticity in the S1 cortex appears within days following nerve injury; however, the underlying cellular mechanisms of this plasticity and whether it has a causal relationship to allodynia remain unsolved. Furthermore, it is not known whether glial activation occurs within the S1 cortex following injury or whether it contributes to this S1 synaptic plasticity. Using in vivo 2-photon imaging with genetic and pharmacological manipulations of murine models, we have shown that sciatic nerve ligation induces a re-emergence of immature metabotropic glutamate receptor 5 (mGluR5) signaling in S1 astroglia, which elicits spontaneous somatic Ca2+ transients, synaptogenic thrombospondin 1 (TSP-1) release, and synapse formation. This S1 astrocyte reactivation was evident only during the first week after injury and correlated with the temporal changes in S1 extracellular glutamate levels and dendritic spine turnover. Blocking the astrocytic mGluR5-signaling pathway suppressed mechanical allodynia, while activating this pathway in the absence of any peripheral injury induced long-lasting (>1 month) allodynia. We conclude that reawakened astrocytes are a key trigger for S1 circuit rewiring and that this contributes to neuropathic mechanical allodynia.
用于改善包括机械性异常性疼痛在内的周围神经性疼痛的长期治疗方法有限。虽然脊髓内的胶质细胞激活和伤害性感受传递改变与机械性异常性疼痛的发病机制有关，但皮质回路的变化也伴随周围神经损伤，并且可能代表额外的治疗靶点。在神经损伤后的数天内，初级体感皮层（S1）中的树突棘可塑性就会出现；然而，这种可塑性的潜在细胞机制以及它与异常性疼痛是否存在因果关系仍未解决。此外，尚不清楚损伤后S1皮层内是否发生胶质细胞激活，或者它是否促成了这种S1突触可塑性。通过对小鼠模型进行基因和药理学操作并结合体内双光子成像，我们发现坐骨神经结扎会诱导S1星形胶质细胞中未成熟代谢型谷氨酸受体5（mGluR5）信号重新出现，这会引发自发的体细胞Ca2+瞬变、促突触形成的血小板反应蛋白1（TSP-1）释放以及突触形成。这种S1星形胶质细胞的重新激活仅在损伤后的第一周内明显，并且与S1细胞外谷氨酸水平和树突棘更新的时间变化相关。阻断星形胶质细胞的mGluR5信号通路可抑制机械性异常性疼痛，而在没有任何周围神经损伤的情况下激活该通路则会诱导持久（>1个月）的异常性疼痛。我们得出结论，重新激活的星形胶质细胞是S1回路重新布线的关键触发因素，并且这促成了神经性机械性异常性疼痛。
