Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
School of Human and Social Sciences, University of West London, London, UK.
Eur J Pharmacol. 2019 Sep 5;858:172475. doi: 10.1016/j.ejphar.2019.172475. Epub 2019 Jun 19.
The development of effective therapeutics for cancer-induced bone pain (CIBP) remains a tremendous challenge owing to its unclear mechanisms. Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central nervous system (CNS). Emerging studies have shown that disinhibition in the spinal cord dorsal horn may account for the development of chronic pain. However, the role of GABA in the development of CIBP remains elusive. In addition, accumulating evidence has shown that neuroglial cells in the peripheral nervous system, especially astrocytes and microglial cells, played an important role in the maintenance of CIBP. In this study, we investigated the expression of GABA and Gamma-aminobutyric acid transporter-1 (GAT-1), a transporter of GABA. Our results demonstrate that GABA was decreased in CIBP rats as expected. However, the expression of glutamic acid decarboxylase (GAD) 65 was up-regulated on day 21 after surgery, while the expression of GAD 67 remained unchanged after surgery. We also found that the expression of GAT-1 was up-regulated mainly in the astrocytes of the spinal cord. Moreover, we evaluated the analgesic effect of exogenous GABA and the GAT-1 inhibitor. Intrathecal administration of exogenous GABA and NO-711 (a GAT-1 selective inhibitor) significantly reversed CIBP-induced mechanical allodynia in a dose-dependent manner. These results firstly show that neuron-glia interactions, especially on the GABAergic pathway, contribute to the development of CIBP. In conclusion, exogenous GABA and GAT-1 inhibitor might be alternative therapeutic strategies for the treatment of CIBP.
癌症骨痛（CIBP）的有效治疗方法的发展仍然是一个巨大的挑战，这是由于其机制尚不清楚。γ-氨基丁酸（GABA）是中枢神经系统（CNS）中的主要抑制性神经递质。新兴的研究表明，脊髓背角的去抑制可能是慢性疼痛发展的原因。然而，GABA 在 CIBP 发展中的作用仍不清楚。此外，越来越多的证据表明，周围神经系统中的神经胶质细胞，特别是星形胶质细胞和小胶质细胞，在维持 CIBP 中发挥了重要作用。在这项研究中，我们研究了 GABA 和 GABA 转运体-1（GAT-1）的表达，GAT-1 是 GABA 的转运体。我们的结果表明，正如预期的那样，CIBP 大鼠中的 GABA 减少了。然而，手术后第 21 天谷氨酸脱羧酶（GAD）65 的表达上调，而手术后 GAD 67 的表达保持不变。我们还发现，GAT-1 的表达主要在上皮细胞中上调脊髓中的星形胶质细胞。此外，我们评估了外源性 GABA 和 GAT-1 抑制剂的镇痛作用。鞘内给予外源性 GABA 和 NO-711（一种 GAT-1 选择性抑制剂）可显著逆转 CIBP 诱导的机械性痛觉过敏，呈剂量依赖性。这些结果首先表明神经元-神经胶质相互作用，特别是 GABA 能途径，有助于 CIBP 的发展。总之，外源性 GABA 和 GAT-1 抑制剂可能是治疗 CIBP 的替代治疗策略。
