GLT1 overexpression reverses established neuropathic pain-related behavior and attenuates chronic dorsal horn neuron activation following cervical spinal cord injury.
GLT1 overexpression reverses established neuropathic pain-related behavior and attenuates chronic dorsal horn neuron activation following cervical spinal cord injury.
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作者：
Falnikar A;Hala TJ;Poulsen DJ;Lepore AC
神经性疼痛的发展发生在创伤性脊髓损伤（SCI）患者的主要部分，导致衰弱和往往长期的身体和心理负担。脊髓损伤后，细胞外谷氨酸稳态的慢性失调在介导疼痛神经传递的浅表背角神经元持续的中枢高兴奋性中起关键作用，导致各种形式的神经性疼痛。星形胶质细胞表达主要的中枢神经系统谷氨酸转运蛋白GLT1，它负责绝大多数的功能性谷氨酸摄取，特别是在脊髓中。在与同侧前爪热超敏性（一种慢性水平神经性疼痛相关行为）相关的小鼠脊髓损伤单侧颈椎挫伤模型中，我们之前报道了GLT1表达和GLT1介导的功能性颈脊髓背角谷氨酸摄取显著且持久的减少。为了治疗颈挫伤脊髓损伤后GLT1功能障碍，我们将腺相关病毒8型(AAV8)-Gfa2载体注入浅表背角，选择性地增加星形胶质细胞中GLT1的表达。与单纯挫伤动物和接受AAV8-eGFP对照注射的损伤小鼠相比，给药AAV8-GLT1增加了损伤颈脊髓背角星形胶质细胞中GLT1蛋白的表达，导致已经建立的热敏反应的显著和持续逆转。此外，注射AAV8-GLT1显著降低了浅表背角神经元中转录因子和持续增加的神经元激活标志物ΔFosB的表达。这些结果表明，局部恢复GLT1在浅表背角的表达是治疗脊髓损伤后慢性神经性疼痛的一个有希望的靶点。
Development of neuropathic pain occurs in a major portion of traumatic spinal cord injury (SCI) patients, resulting in debilitating and often long-term physical and psychological burdens. Following SCI, chronic dysregulation of extracellular glutamate homeostasis has been shown to play a key role in persistent central hyperexcitability of superficial dorsal horn neurons that mediate pain neurotransmission, leading to various forms of neuropathic pain. Astrocytes express the major CNS glutamate transporter, GLT1, which is responsible for the vast majority of functional glutamate uptake, particularly in the spinal cord. In our unilateral cervical contusion model of mouse SCI that is associated with ipsilateral forepaw heat hypersensititvity (a form of chronic at-level neuropathic pain-related behavior), we previously reported significant and long-lasting reductions in GLT1 expression and functional GLT1-mediated glutamate uptake in cervical spinal cord dorsal horn. To therapeutically address GLT1 dysfunction following cervical contusion SCI, we injected an adeno-associated virus type 8 (AAV8)-Gfa2 vector into the superficial dorsal horn to increase GLT1 expression selectively in astrocytes. Compared to both contusion-only animals and injured mice that received AAV8-eGFP control injection, AAV8-GLT1 delivery increased GLT1 protein expression in astrocytes of the injured cervical spinal cord dorsal horn, resulting in a significant and persistent reversal of already-established heat hypersensitivity. Furthermore, AAV8-GLT1 injection significantly reduced expression of the transcription factor and marker of persistently increased neuronal activation, ΔFosB, in superficial dorsal horn neurons. These results demonstrate that focal restoration of GLT1 expression in the superficial dorsal horn is a promising target for treating chronic neuropathic pain following SCI.