Inhibition of Glycine Re-Uptake: A Potential Approach for Treating Pain by Augmenting Glycine-Mediated Spinal Neurotransmission and Blunting Central Nociceptive Signaling.
Inhibition of Glycine Re-Uptake: A Potential Approach for Treating Pain by Augmenting Glycine-Mediated Spinal Neurotransmission and Blunting Central Nociceptive Signaling.
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DOI：
10.3390/biom11060864
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发表时间：
2021-06-10
期刊：
影响因子：
5.5
通讯作者：
Cioffi CL
中科院分区：
文献类型：
--
作者：
Cioffi CL
在众多导致病理性疼痛的细胞和分子过程中，脊髓伤害性信号传递到高级皮质中枢的去抑制起着关键作用。重要的是，有证据表明，在炎症性和神经病理性疼痛模型中，甘氨酸能神经传递受损发生在脊髓背角，是导致机械性痛觉过敏和痛觉异常的关键适应不良机制。因此，有人推测，能够增强背角甘氨酸能张力的药物可能能够钝化或阻断到大脑的异常伤害性感受器信号，并作为一类新的止痛剂用于各种病理性疼痛状态。事实上，增强功能障碍的甘氨酸能传递的药物，特别是甘氨酸转运体的抑制剂(GlyT1和GlyT2)，作为一类潜在的新型止痛药正引起广泛的兴趣。GlyT是溶质载体6(SLC6)家族的钠/氯依赖的−转运体，其抑制可能是增加脊髓细胞外甘氨酸浓度和增强GlyR介导的抑制性神经传递的可能机制。GlyT1和GlyT2的各种抑制剂在几种急性和慢性疼痛的临床前模型中都显示了广泛的止痛效果，为提供一流的非阿片类止痛剂提供了希望，其作用机制与当前的治疗标准不同。本综述将重点介绍GlyT抑制剂作为一类新型止痛药的治疗潜力，介绍该领域的最新进展，并讨论将GlyT抑制剂开发为安全有效的止痛剂所面临的关键挑战。
Among the myriad of cellular and molecular processes identified as contributing to pathological pain, disinhibition of spinal cord nociceptive signaling to higher cortical centers plays a critical role. Importantly, evidence suggests that impaired glycinergic neurotransmission develops in the dorsal horn of the spinal cord in inflammatory and neuropathic pain models and is a key maladaptive mechanism causing mechanical hyperalgesia and allodynia. Thus, it has been hypothesized that pharmacological agents capable of augmenting glycinergic tone within the dorsal horn may be able to blunt or block aberrant nociceptor signaling to the brain and serve as a novel class of analgesics for various pathological pain states. Indeed, drugs that enhance dysfunctional glycinergic transmission, and in particular inhibitors of the glycine transporters (GlyT1 and GlyT2), are generating widespread interest as a potential class of novel analgesics. The GlyTs are Na+/Cl−-dependent transporters of the solute carrier 6 (SLC6) family and it has been proposed that the inhibition of them presents a possible mechanism by which to increase spinal extracellular glycine concentrations and enhance GlyR-mediated inhibitory neurotransmission in the dorsal horn. Various inhibitors of both GlyT1 and GlyT2 have demonstrated broad analgesic efficacy in several preclinical models of acute and chronic pain, providing promise for the approach to deliver a first-in-class non-opioid analgesic with a mechanism of action differentiated from current standard of care. This review will highlight the therapeutic potential of GlyT inhibitors as a novel class of analgesics, present recent advances reported for the field, and discuss the key challenges associated with the development of a GlyT inhibitor into a safe and effective agent to treat pain.
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影响因子：
16.2
作者：
Foster, Edmund;Wildner, Hendrik;Tudeau, Laetitia;Haueter, Sabine;Ralvenius, William T.;Jegen, Monika;Johannssen, Helge;Hoesli, Ladina;Haenraets, Karen;Ghanem, Alexander;Conzelmann, Karl-Klaus;Boesl, Michael;Zeilhofer, Hanns Ulrich
通讯作者：
Zeilhofer, Hanns Ulrich
影响因子：
3.7
作者：
Bogdanik LP;Chapman HD;Miers KE;Serreze DV;Burgess RW
通讯作者：
Burgess RW
影响因子：
16.2
作者：
BOROWSKY, B;MEZEY, E;HOFFMAN, BJ
通讯作者：
HOFFMAN, BJ
影响因子：
5.5
作者：
Bradaïa, A;Schlichter, R;Trouslard, J
通讯作者：
Trouslard, J
影响因子：
13.9
作者：
Costigan M;Scholz J;Woolf CJ
通讯作者：
Woolf CJ