Spinal glutamate uptake is critical for maintaining normal sensory transmission in rat spinal cord
Spinal glutamate uptake is critical for maintaining normal sensory transmission in rat spinal cord
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DOI：
10.1016/j.pain.2005.02.006
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发表时间：
2005-05-01
期刊：
影响因子：
7.4
通讯作者：
Tao, YX
中科院分区：
文献类型：
--
作者：
Liaw, WJ;Stephens, RL;Tao, YX
谷氨酸是初级传入终末的主要兴奋性神经递质，对正常的脊髓兴奋性突触传递至关重要。然而，对生理条件下脊髓内突触释放谷氨酸的调节知之甚少。钠依赖的高亲和力谷氨酸转运体是清除突触释放的谷氨酸的主要机制。在本研究中，我们发现鞘内注射谷氨酸转运体阻断剂DL-苏氨酸-β-苄氧基天冬氨酸(TBOA)和二氢海人酸能产生显著的和剂量依赖的自发伤害性行为，如舔、抖动和尾部定向咬人，这些现象类似于鞘内谷氨酸受体激动剂引起的行为。鞘内TBOA还导致对热刺激和机械刺激的显著超敏反应。鞘内注射N-甲基-D-天冬氨酸受体拮抗剂MK-801和AP-5、非N-甲基-D-天门冬氨酸受体拮抗剂CNQX或一氧化氮合酶抑制剂L-NAME可显著阻断上述行为反应。体内微透析分析显示，鞘内注射TBOA后，脊髓细胞外谷氨酸浓度短期内升高。此外，在脊髓背侧表面局部应用TBOA后，体内谷氨酸伏安法显示细胞外谷氨酸浓度显著升高。目前的研究表明，谷氨酸转运体抑制引起的脊髓谷氨酸摄取缺陷会导致谷氨酸在脊髓中过度蓄积。后者导致突触谷氨酸受体持续过度激活，产生自发的伤害性行为和感觉超敏。我们的结果表明，在生理条件下，通过脊髓谷氨酸转运体摄取谷氨酸对于维持正常的感觉传递至关重要。(C)2005年国际疼痛研究协会。爱思唯尔出版，版权所有。
Glutamate is a major excitatory neurotransmitter in primary afferent terminals and is critical for normal spinal excitatory synaptic transmission. However, little is known about the regulation of synaptically released glutamate in the spinal cord under physiologic conditions. The sodium-dependent, high-affinity glutamate transporters are the primary mechanism for the clearance of synaptically released glutamate. In the present study, we found that intrathecal injection of glutamate transporter blockers DL-threo-beta-benzyloxyaspartate (TBOA) and dihydrokainate produced significant and dose-dependent spontaneous nociceptive behaviors, such as licking, shaking, and caudally directed biting, phenomena similar to the behaviors caused by intrathecal glutamate receptor agonists. Intrathecal TBOA also led to remarkable hypersensitivity in response to thermal and mechanical stimuli. These behavioral responses could be significantly blocked by intrathecal injection of the NMDA receptor antagonists MK-801 and AP-5, the non-NMDA receptor antagonist CNQX or the nitric oxide synthase inhibitor L-NAME. In vivo microdialysis analysis showed short-term elevation of extracellular glutamate concentration in the spinal cord after intrathecal injection of TBOA. Furthermore, topical application of TBOA on the dorsal surface of the spinal cord resulted in a significant elevation of extracellular glutamate concentration demonstrated by in vivo glutamate voltametry. The present study indicates that defective spinal glutamate uptake caused by inhibition of glutamate transporters leads to excessive glutamate accumulation in the spinal cord. The latter results in persistent over-activation of synaptic glutamate receptors, producing spontaneous nociceptive behaviors and sensory hypersensitivity. Our results suggest that glutamate uptake through spinal glutamate transporters is critical for maintaining normal sensory transmission under physiologic conditions. (c) 2005 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.