Neuronal allodynic mechanisms of Slc7a5 (LAT1) in the spared nerve injury rodent model of neuropathic pain.
Neuronal allodynic mechanisms of Slc7a5 (LAT1) in the spared nerve injury rodent model of neuropathic pain.
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DOI：
10.1007/s00424-021-02653-9
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发表时间：
2022-04
期刊：
影响因子：
--
通讯作者：
Alles SRA
中科院分区：
文献类型：
--
作者：
Goins AE;Gomez K;Ran D;Afaghpour-Becklund M;Khanna R;Alles SRA
在美国和全球范围内，每5名患者中就有1名患有高影响性慢性疼痛。有效的，非成瘾性的，非阿片类药物治疗慢性疼痛的治疗是迫切需要的。Slc 7a 5（Lat 1），也称为系统L-中性氨基酸转运蛋白，参与许多与炎症相关的生理过程。转录组学研究表明，Slc 7a 5及其结合伴侣Slc 3a 2在背根神经节（DRG）和脊髓背角的神经元中表达，这对慢性疼痛的伤害感受和病理生理学的启动和维持至关重要。此外，Slc 7a 5是一线抗异常性疼痛的加巴喷丁类药物的转运蛋白，并与涉及伤害感受和慢性疼痛的离子通道结合，包括电压门控钠通道Nav1.7和电压门控钾通道Kv1.1和Kv1.2。我们发现，在神经病理性疼痛的保留神经损伤（SNI）啮齿动物模型中，通过鞘内施用药物JPH 203来阻断Slc 7a 5减轻了异常性疼痛。Western印迹和免疫组织化学研究显示，与对照小鼠相比，SNI小鼠的脊髓和DRG中Slc 7a 5蛋白水平增加。使用全细胞电流钳电生理学，我们观察到JPH 203处理降低SNI小鼠小直径（<30 μm）DRG神经元的兴奋性，与其行为效应一致。JPH 203处理的未处理大鼠DRG的电压钳记录确定了对河豚毒素抗性（TTX-R）钠电流的影响。总之，这些结果表明Slc 7a 5在慢性神经性疼痛中失调，并且可以靶向提供超敏反应的缓解。
High-impact chronic pain is suffered by 1 in 5 patients in the US and globally. Effective, non-addictive, non-opioid therapeutics are urgently needed for the treatment of chronic pain. Slc7a5 (Lat1), also known as system L-neutral amino acid transporter, is involved in a number of physiological processes related to inflammation. Transcriptomics studies have shown that Slc7a5 and its binding partner Slc3a2 are expressed in neurons of the dorsal root ganglia (DRG) and spinal dorsal horn, which are critical to the initiation and maintenance of nociception and pathophysiology of chronic pain. In addition, Slc7a5 is a transporter for the first-line anti-allodynic gabapentinoid drugs and binds to ion channels implicated in nociception and chronic pain including the voltage-gated sodium channel Nav1.7 and the voltage-gated potassium channels Kv1.1 and Kv1.2. We found that blocking Slc7a5 with intrathecal administration of the drug JPH203 alleviated allodynia in the spared nerve injury (SNI) rodent model of neuropathic pain. Western blot and immunohistochemistry studies revealed an increase in Slc7a5 protein levels in the spinal cord and DRGs of SNI mice compared to control mice. Using whole-cell current clamp electrophysiology, we observed that JPH203 treatment reduced excitability of small-diameter (<30 μm) DRG neurons from SNI mice, in agreement with its behavioral effects. Voltage-clamp recordings from JPH203-treated naïve rat DRGs identified an effect on tetrodotoxin-resistant (TTX-R) sodium currents. Altogether, these results demonstrate that Slc7a5 is dysregulated in chronic neuropathic pain and can be targeted to provide relief of hypersensitivity.
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