Neuropathic pain is among the most common and difficult-to-treat types of chronic pain and is associated with sodium channel malfunction. The sodium channel blocker ralfinamide has exhibited potent analgesic effects in several preclinical pain models and in patients with mixed neuropathic pain syndromes (Phase II trials), but it failed to ameliorate neuropathic low back pain in Phase III trials. It is unclear whether ralfinamide is effective against neuropathic pain induced by specified etiologies. In the present study, the antinociceptive effects of ralfinamide in neuropathic pain models induced by spared nerve injury and chemotherapy were compared in a gabapentin-controlled manner. The effects of ralfinamide on physiological pain were evaluated in mechanical withdrawal, hot plate, and acetic acid writhing tests. We also investigated the effects of ralfinamide on cardiovascular function and locomotor activity. Oral ralfinamide dose-dependently alleviated spared nerve injury-induced allodynia in rats and mice. Ralfinamide increased mechanical withdrawal thresholds in oxaliplatin-induced and paclitaxel-induced neuropathic pain. Ralfinamide did not affect physiological pain, locomotion, or cardiovascular function. Together, ralfinamide attenuated mechanical allodynia in all the neuropathic pain models tested, with subtle differences in efficacy. The effect of ralfinamide is comparable to that of gabapentin, but with no interference in basal mechanical sensitivity. The present study supports the effectiveness of selective sodium channel blockade as an analgesic strategy, as well as the development of compounds similar to ralfinamide.

中文翻译：

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雷非酰胺对神经损伤和化学疗法诱发的神经性疼痛模型的影响。

神经性疼痛是慢性疼痛中最常见且最难以治疗的类型，并与钠通道功能障碍相关。钠通道阻滞剂雷非酰胺在几种临床前疼痛模型和混合性神经性疼痛综合征患者中显示出有效的镇痛作用（II期试验），但在III期试验中未能缓解神经性下腰痛。尚不清楚雷非酰胺对由特定病因引起的神经性疼痛是否有效。在本研究中，以加巴喷丁控制的方式比较了雷非酰胺在神经损伤和化学疗法诱发的神经性疼痛模型中的镇痛作用。在机械停药，热板和乙酸扭体试验中评估了雷非酰胺对生理性疼痛的影响。我们还研究了雷非酰胺对心血管功能和运动活动的影响。口服雷非酰胺的剂量依赖性地减轻了大鼠和小鼠中多余的神经损伤引起的异常性疼痛。Ralfinamide增加了奥沙利铂和紫杉醇引起的神经性疼痛的机械退缩阈值。雷非酰胺不影响生理疼痛，运动或心血管功能。总之，雷非酰胺可减轻所有测试的神经性疼痛模型的机械性异常性疼痛，但疗效存在细微差别。雷非酰胺的作用与加巴喷丁相当，但对基础机械敏感性无干扰。本研究支持选择性钠通道阻滞作为镇痛策略的有效性，以及类似于雷非酰胺的化合物的开发。