Department of Pharmacodynamics, Semmelweis University, 4 Nagyvárad tér, H-1089 Budapest, Hungary.
Department of Pharmacology and Pharmacotherapy, Semmelweis University, 4 Nagyvárad tér, H-1089 Budapest, Hungary.
Int J Mol Sci. 2022 Aug 24;23(17):9564. doi: 10.3390/ijms23179564.
Current treatment approaches to manage neuropathic pain have a slow onset and their use is largely hampered by side-effects, thus there is a significant need for finding new medications. Tolperisone, a centrally acting muscle relaxant with a favorable side effect profile, has been reported to affect ion channels, which are targets for current first-line medications in neuropathic pain. Our aim was to explore its antinociceptive potency in rats developing neuropathic pain evoked by partial sciatic nerve ligation and the mechanisms involved. Acute oral tolperisone restores both the decreased paw pressure threshold and the elevated glutamate level in cerebrospinal fluid in neuropathic rats. These effects were comparable to those of pregabalin, a first-line medication in neuropathy. Tolperisone also inhibits release of glutamate from rat brain synaptosomes primarily by blockade of voltage-dependent sodium channels, although inhibition of calcium channels may also be involved at higher concentrations. However, pregabalin fails to affect glutamate release under our present conditions, indicating a different mechanism of action. These results lay the foundation of the avenue for repurposing tolperisone as an analgesic drug to relieve neuropathic pain.
目前治疗神经性疼痛的方法起效缓慢，且副作用大，因此需要寻找新的药物。托哌酮是一种具有良好副作用谱的中枢作用肌肉松弛剂，据报道它可以影响离子通道，而离子通道是神经性疼痛一线药物的作用靶点。我们的目的是探索托哌酮在部分坐骨神经结扎诱导的神经性疼痛大鼠中的镇痛作用及其机制。急性口服托哌酮可恢复神经性疼痛大鼠的足底压力阈值降低和脑脊液中谷氨酸水平升高。这些作用与一线治疗神经病变的药物普瑞巴林相当。托哌酮也可通过阻断电压依赖性钠通道抑制谷氨酸从大鼠脑突触小体释放，尽管在较高浓度时钙通道的抑制也可能参与其中。然而，普瑞巴林在我们目前的条件下不能影响谷氨酸的释放，表明其作用机制不同。这些结果为将托哌酮重新用作缓解神经性疼痛的镇痛药开辟了途径。
