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Functional role and therapeutic potential of the glycine transporter GlyT1 in chronic pain

甘氨酸转运蛋白 GlyT1 在慢性疼痛中的功能作用和治疗潜力

基本信息

批准号：
324595044
负责人：
Professor Dr. Volker Eulenburg
金额：
--
依托单位：
Klinik für Anästhesiologie und Operative Intensivmedizin
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2016
资助国家：
德国
起止时间：
2015-12-31 至 2020-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/324595044?language=en
关键词：
Functional role therapeutic potential glycine

项目摘要

The main function of pain perception is to protect organisms from damage caused by noxious stimuli. Maladaptive plasticity within the nociceptive system can result in allodynia and/or hyperalgesia. Under these conditions pain loses its protective role, and is considered as anautonomous disease in itself. Despite extensive suffering of affected patients and intense research over decades, the neuronal mechanisms leading to these chronic pain conditions pain are still only poorly understood and treatment options remain rather unsatisfying. In recent approaches, the restoration of inhibitory neurotransmission within the dorsal horn of spinal cord has been a major aim for the development of new treatment options for chronic pain conditions.The enhancement of GABAergic neurotransmission, however, has proven difficult in part due to the high abundance of GABAA receptors in higher brain regions that cause unfavourable side effects. Since glycinergic neurotransmission is largely restricted to caudal parts of the central nervous system, similar central side effects are not to be expected. Therefore, the glycinergic system seems to be a promising novel target for therapeutic approaches against chronic pain. We have shown previously that pharmacological reduction of the glycine transporter 1 (GlyT1) glycine uptake activity efficiently reduces the facilitated pain response in animal models of neuropathic as well as inflammatory pain. In this project we aim to elucidate the mechanisms how inhibition of GlyT1 ameliorates chronic pain by an interdisciplinary project combining molecular biological and histological as well as neurophysiological approaches.In detail, we plan to make use of a mouse line that carries a modified GlyT1 allele allowing the Cre recombinase mediated inactivation of GlyT1 expression. By stable transgenic or viral induced expression of Cre recombinase in mice of this mouse line we plan to obtain a cell type and/or regions specific GlyT1 deficiency. In these mice, we plan first to determine the consequences of GlyT1 deficiency on glycine dependent inhibitory and excitatory neurotransmission by an electrophysiological approach in dorsal horn neurons. Subsequently we plan to induce neuropathic or inflammatory pain conditions in these mice and determine the neuroplastic changes that accompany the chronification of pain, by biochemical, histological and electrophysiological methods. Comparison to wild-type animals will reveal the inpact of the respective GlyT1 population on the effects of Glyt1 active substances in the context of chonic pain. Taken together this project will provide new information on the cell type specific functions of GlyT1 within the spinal cord both under physiological conditions and under the influence of chronic pain. This will provide new insight on the mechanism by which substances acting on GlyT1 influence chronic pain.

痛觉的主要功能是保护生物体免受有害刺激的损害。伤害性感觉系统中的不适应可塑性可导致痛觉过敏和/或痛觉过敏。在这种情况下，疼痛失去了保护作用，本身就被认为是一种自主疾病。尽管几十年来，受影响的患者遭受了广泛的痛苦，并进行了大量的研究，但导致这些慢性疼痛状况的神经机制仍然知之甚少，治疗方案仍然相当不令人满意。在最近的方法中，恢复脊髓背角内的抑制性神经传递一直是发展慢性疼痛条件下新的治疗方案的主要目标。然而，事实证明，增强GABAA能神经传递是困难的，部分原因是在较高的脑区GABAA受体的高度丰富，导致不利的副作用。由于甘氨酸能神经传递在很大程度上局限于中枢神经系统的尾部，类似的中枢副作用是不可预期的。因此，甘氨酸能系统似乎是治疗慢性疼痛的一个有前途的新靶点。我们以前已经证明，在神经病理性和炎症性疼痛的动物模型中，药物降低甘氨酸转运蛋白1(GlyT1)的甘氨酸摄取活性可以有效地减少促进疼痛反应。在这个项目中，我们旨在通过一个结合了分子生物学、组织学和神经生理学方法的跨学科项目来阐明抑制GlyT1如何缓解慢性疼痛的机制。具体来说，我们计划利用一个携带修饰的GlyT1等位基因的小鼠系，允许Cre重组酶介导的GlyT1表达失活。通过稳定的转基因或病毒诱导表达Cre重组酶，我们计划获得一种细胞类型和/或区域特异性的GlyT1缺陷。在这些小鼠中，我们计划首先通过电生理学方法确定GlyT1缺乏对甘氨酸依赖性抑制和兴奋性神经传递的影响。随后，我们计划在这些小鼠中诱导神经病理性或炎症性疼痛，并通过生化、组织学和电生理学方法确定伴随疼痛慢性化的神经可塑性变化。与野生型动物的比较将揭示各自的GlyT1种群对Glyt1活性物质在软骨痛背景下的影响。综上所述，该项目将提供关于GlyT1在生理条件下和慢性疼痛影响下脊髓内细胞类型特定功能的新信息。这将为作用于GlyT1的物质影响慢性疼痛的机制提供新的见解。