Gegelashvili Georgi, Bjerrum Ole Jannik
Institute of Chemical Biology, Ilia State University, K. Cholokashvili Ave 3/5, 0162, Tbilisi, Georgia.
Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, 2100, Denmark.
Adv Neurobiol. 2017;16:225-253. doi: 10.1007/978-3-319-55769-4_11.
The vast majority of peripheral neurons sensing noxious stimuli and conducting pain signals to the dorsal horn of the spinal cord utilize glutamate as a chemical transmitter of excitation. High-affinity glutamate transporter subtypes GLAST/EAAT1, GLT1/EAAT2, EAAC1/EAAT3, and EAAT4, differentially expressed on sensory neurons, postsynaptic spinal interneurons, and neighboring glia, ensure fine modulation of glutamate neurotransmission in the spinal cord. The glutamate transport system seems to play important roles in molecular mechanisms underlying chronic pain and analgesia. Downregulation of glutamate transporters (GluTs) often precedes or occurs simultaneously with development of hypersensitivity to thermal or tactile stimuli in various models of chronic pain. Moreover, antisense knockdown or pharmacological inhibition of these membrane proteins can induce or aggravate pain. In contrast, upregulation of GluTs by positive pharmacological modulators or by viral gene transfer to the spinal cord can reverse the development of such pathological hypersensitivity. Furthermore, some multi-target drugs displaying analgesic properties (e.g., tricyclic antidepressant amitriptyline, riluzole, anticonvulsant valproate, tetracycline antibiotic minocycline, β-lactam antibiotic ceftriaxone and its structural analog devoid of antibacterial activity, clavulanic acid) can significantly increase the spinal glutamate uptake. Thus, mounting evidence points at GluTs as prospective therapeutic target for chronic pain treatment. However, design and development of new analgesics based on the modulation of glutamate uptake will require more precise knowledge of molecular mechanisms underlying physiological or aberrant functioning of this transport system in the spinal cord.
绝大多数感知有害刺激并将疼痛信号传导至脊髓背角的外周神经元利用谷氨酸作为兴奋性化学递质。高亲和力谷氨酸转运体亚型GLAST/EAAT1、GLT1/EAAT2、EAAC1/EAAT3和EAAT4在感觉神经元、脊髓后突触中间神经元及相邻神经胶质细胞上差异表达，确保脊髓中谷氨酸神经传递的精细调节。谷氨酸转运系统似乎在慢性疼痛和镇痛的分子机制中发挥重要作用。在各种慢性疼痛模型中，谷氨酸转运体（GluTs）的下调通常先于对热或触觉刺激的超敏反应出现或与之同时发生。此外，对这些膜蛋白进行反义敲低或药理学抑制可诱导或加重疼痛。相反，通过阳性药理学调节剂或病毒基因转移至脊髓使GluTs上调可逆转这种病理性超敏反应的发展。此外，一些具有镇痛特性的多靶点药物（如三环类抗抑郁药阿米替林、利鲁唑、抗惊厥药丙戊酸盐、四环素抗生素米诺环素、β-内酰胺抗生素头孢曲松及其无抗菌活性的结构类似物克拉维酸）可显著增加脊髓对谷氨酸的摄取。因此，越来越多的证据表明GluTs是慢性疼痛治疗的潜在治疗靶点。然而，基于谷氨酸摄取调节设计和开发新的镇痛药将需要更精确地了解该转运系统在脊髓中生理或异常功能的分子机制。
