Blocking the GABA transporter GAT-1 ameliorates spinal GABAergic disinhibition and neuropathic pain induced by paclitaxel.
Blocking the GABA transporter GAT-1 ameliorates spinal GABAergic disinhibition and neuropathic pain induced by paclitaxel.
复制标题
DOI：
10.1111/jnc.13103
复制
发表时间：
2015-06
影响因子：
4.7
通讯作者：
Weng HR
中科院分区：
文献类型：
--
作者：
Yadav R;Yan X;Maixner DW;Gao M;Weng HR
紫杉醇是一种广泛用于肿瘤治疗的化疗药物。接受紫杉醇治疗的患者通常会出现神经性疼痛，生活质量下降，这阻碍了这种救命药物的使用。在这项研究中，我们通过行为测试、电生理学和生化技术确定了GABA转运体在紫杉醇诱导的神经性疼痛发生中的作用。我们发现紫杉醇引起的神经性疼痛大鼠脊髓背角强直性GABA受体活性降低。在正常对照中，GABA受体活性主要受GABA转运体GAT-1控制，而不受GAT-3控制。在脊髓背角，GAT-1在突触前终末和星形胶质细胞中表达，而GAT-3仅在星形胶质细胞中表达。在紫杉醇诱导的神经性疼痛大鼠中，GAT-1蛋白表达升高，GAT-3蛋白表达降低。这与全球GABA摄取增加同时相关。通过阻断GAT-1转运体而非GAT-3转运体，紫杉醇诱导的gabat - tonic抑制的衰减得到改善。鞘内注射GAT-1抑制剂可明显减轻紫杉醇引起的神经性疼痛。这些发现表明，靶向GAT-1转运蛋白逆转脊髓背角的去抑制可能是治疗紫杉醇诱导的神经性疼痛的有效方法。
Paclitaxel is a chemotherapeutic agent widely used for treating carcinomas. Patients receiving paclitaxel often develop neuropathic pain and have a reduced quality of life which hinders the use of this life-saving drug. In this study, we determined the role of GABA transporters in the genesis of paclitaxel-induced neuropathic pain using behavioral tests, electrophysiology, and biochemical techniques. We found that tonic GABA receptor activities in the spinal dorsal horn were reduced in rats with neuropathic pain induced by paclitaxel. In normal controls, tonic GABA receptor activities were mainly controlled by the GABA transporter GAT-1 but not GAT-3. In the spinal dorsal horn, GAT-1 was expressed at presynaptic terminals and astrocytes while GAT-3 was only expressed in astrocytes. In rats with paclitaxel-induced neuropathic pain, the protein expression of GAT-1 was increased while GAT-3 was decreased. This was concurrently associated with an increase of global GABA uptake. The paclitaxel-induced attenuation of GABAergic tonic inhibition was ameliorated by blocking GAT-1 but not GAT-3 transporters. Paclitaxel-induced neuropathic pain was significantly attenuated by the intrathecal injection of a GAT-1 inhibitor. These findings suggest that targeting GAT-1 transporters for reversing disinhibition in the spinal dorsal horn may be a useful approach for treating paclitaxel-induced neuropathic pain.
登录
查看更多内容
影响因子：
5.5
作者：
Hugel, S;Schlichter, R
通讯作者：
Schlichter, R
影响因子：
5.2
作者：
Bardoni R;Takazawa T;Tong CK;Choudhury P;Scherrer G;Macdermott AB
通讯作者：
Macdermott AB
影响因子：
2.5
作者：
Gosselin, Romain-Daniel;Bebber, Damien;Decosterd, Isabelle
通讯作者：
Decosterd, Isabelle
影响因子：
56.9
作者：
GUASTELLA, J;NELSON, N;KANNER, BI
通讯作者：
KANNER, BI
CX3CL1介导的巨噬细胞激活导致紫杉醇诱导的DRG神经元凋亡和疼痛性周围神经病变
影响因子：
15.1
作者：
Huang, Zhen-Zhen;Li, Dai;Xin, Wen-Jun
通讯作者：
Xin, Wen-Jun