Glucocorticoid regulation of lactate release from spinal astrocytes contributes to the induction of spinal LTP of C-fiber-evoked field potentials and the development of mechanical allodynia
Glucocorticoid regulation of lactate release from spinal astrocytes contributes to the induction of spinal LTP of C-fiber-evoked field potentials and the development of mechanical allodynia
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糖皮质激素对脊髓星形胶质细胞乳酸释放的调节有助于诱导 C 纤维诱发场电位的脊髓 LTP 和机械性异常性疼痛的发生
DOI：
10.1016/j.neuropharm.2022.109253
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发表时间：
2022-09
影响因子：
4.7
通讯作者：
Xuhong Wei
中科院分区：
文献类型：
--
作者：
Ruizhen Huang;Shuang Han;Yuxin Qiu;Taihe Zhou;Yuning Wu;Hongchun Du;Jing Xu;Xuhong Wei
坐骨神经的高频刺激 (HFS) 会导致 C 纤维突触的长时程增强 (LTP) 和持久的疼痛超敏反应。然而，其根本机制仍不清楚。在本研究中，我们使用 Sprague-Dawley 大鼠和任一性别的 Aldh1L1-CreERT2 小鼠研究了糖皮质激素 (GC) 分泌到血浆后星形胶质细胞衍生的 1-乳酸在脊髓背角的参与情况。我们发现 HFS 增加了脊髓背角中的 1-乳酸和单羧酸转运蛋白 1/2 (MCT1/2)。抑制糖原分解或阻断乳酸转运可阻止 HFS 后脊髓 LTP 的诱导。此外，HFS 激活的背角星形胶质细胞的化学遗传学抑制可预防脊髓 LTP，减轻机械性异常性疼痛，并降低 HFS 后背角中 L-乳酸水平和 GFAP 表达。相比之下，幼稚大鼠背角星形胶质细胞的化学遗传学激活诱导脊髓 LTP 以及机械异常性疼痛，并增加 GFAP 表达和 L-乳酸。将 L-乳酸直接施用于初始大鼠的脊髓可诱导脊髓 LTP、机械性异常性疼痛和 p-ERK 脊髓表达增加。重要的是，HFS增加了血浆中的GC和脊髓星形胶质细胞中糖皮质激素受体（GR）的表达，肾上腺切除术或使用Cre-Loxp系统敲低星形胶质细胞中的GR可阻断机械性异常性疼痛，防止HFS后脊髓LTP和乳酸的增强。这些结果表明，糖皮质激素释放到血浆中后，脊髓星形胶质细胞释放的乳酸增强了 C 纤维突触的突触传递，是慢性疼痛的基础。
High-frequency stimulation (HFS) of the sciatic nerve leads to long-term potentiation (LTP) at C-fiber synapse and long-lasting pain hypersensitivity. The underlying mechanisms, however, are still unclear. In the present study, we investigated the involvement of astrocytes derivedl-lactate in the spinal dorsal horn subsequent to glucocorticoid (GC) secretion into the plasma in this process using Sprague-Dawley rats and Aldh1L1-CreERT2mice of either sex. We found that HFS increasedl-lactate and monocarboxylate transporters 1/2 (MCT1/2) in the spinal dorsal horn. Inhibition of glycogenolysis or blocking lactate transport prevented the induction of spinal LTP following HFS. Furthermore, Chemogenetical inhibition of dorsal horn astrocytes, which were activated by HFS, prevented spinal LTP, alleviated the mechanical allodynia and the decreased the level l-lactate and GFAP expression in the dorsal horn following HFS. In contrast, Chemogenetics activation of dorsal horn astrocytes in naïve rats induced spinal LTP as well as mechanical allodynia, and increased GFAP expression and l-lactate. Application of l-lactate directly to the spinal cord of naïve rats induced spinal LTP, mechanical allodynia, and increased spinal expression of p-ERK. Importantly, HFS increased GC in the plasma and glucocorticoid receptor (GR) expression in spinal astrocytes, adrenalectomy or knocking down of GR in astrocytes by using Cre-Loxp system blocked the mechanical allodynia, prevented the spinal LTP and the enhancement of lactate after HFS. These results show that lactate released from spinal astrocytes following glucocorticoid release into the plasma enhance synaptic transmission at the C-fiber synapse and underlie pain chronicity.
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影响因子：
15.1
作者：
Alexander, Jessica K.;DeVries, A. Courtney;Kigerl, Kristina A.;Dahlman, Jason M.;Popovich, Phillip G.
通讯作者：
Popovich, Phillip G.
影响因子：
16.2
作者：
Srinivasan R;Lu TY;Chai H;Xu J;Huang BS;Golshani P;Coppola G;Khakh BS
通讯作者：
Khakh BS
影响因子：
2.2
作者：
JENSEN, JC;BURESH, C;NORTON, JA
通讯作者：
NORTON, JA
小胶质细胞 P2X7 受体和下游信号通路参与脊髓伤害性反应的长期增强
影响因子：
15.1
作者：
Chu, Yu-Xia;Zhang, Yan;Zhao, Zhi-Qi
通讯作者：
Zhao, Zhi-Qi
影响因子：
5.3
作者：
Femenia, Teresa;Gimenez-Cassina, Alfredo;Gomez-Galan, Marta
通讯作者：
Gomez-Galan, Marta