Ralfinamide administered orally before hindpaw neurectomy or postoperatively provided long-lasting suppression of spontaneous neuropathic pain-related behavior in the rat
Ralfinamide administered orally before hindpaw neurectomy or postoperatively provided long-lasting suppression of spontaneous neuropathic pain-related behavior in the rat
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DOI：
10.1016/j.pain.2008.04.020
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发表时间：
2008-10-15
期刊：
影响因子：
7.4
通讯作者：
Seltzer, Ze'ev
中科院分区：
文献类型：
--
作者：
Zhang, Shi-Hong;Blech-Hermoni, Yotam;Seltzer, Ze'ev
在刺激诱发慢性疼痛的啮齿动物模型中，单次给药时，雷非酰胺具有镇痛作用。然而，目前尚不清楚神经损伤后长期应用它是否可以抑制自发性慢性疼痛，这是驱使患者寻求治疗的主要症状。在这项研究中，大鼠接受了与疼痛患者产生镇痛作用的血浆水平相似的剂量的雷非酰胺给药。在自割术上测试镇痛效果，自割术是模拟自发性神经性疼痛的去神经爪子的自残行为。对Sprague-Dawley雄性大鼠（N = 10-20/组）进行单侧坐骨神经和隐神经横切。术前口服雷非胺或其溶剂7天（80 mg/kg; bid），然后口服溶剂或雷非胺，直至术后第42天。每天对自切术进行评分，直至第63天。在术前用ralfinamide治疗的ats中发现了持久的“超前镇痛”，表现为延迟的自切发作（P = 0.009）和d 63评分降低（P = 0.01）。从手术至第42天（但术前未接受）接受雷非酰胺（30或60 mg/kg; bid）治疗的大鼠也显示延迟性自切（分别为P = 0.05，P = 0.001）。神经性疼痛相关行为的抑制可能是由ralfinamide报告的机制组合引起的，包括抑制Nav1.3、Nav1.7中的Na+和Ga++电流。Nav1.8和Cav2.2通道，抑制脊髓突触体P物质释放。NMDA受体拮抗和神经保护。(C)2008年国际疼痛研究协会。Elsevier B. V.出版，保留所有权利。
Ralfinamide is analgesic when applied as a single dose in rodent models of stimulus-evoked chronic pain. However, it is unknown whether its chronic application after nerve injury can suppress spontaneous chronic pain, the main symptom driving patients to seek treatment. In this study ralfinamide was administered to rats at doses producing plasma levels similar to those causing analgesia in pain patients. The analgesic effect was tested on autotomy, a behavior of self-mutilation of a denervated paw that models spontaneous neuropathic pain. Sprague-Dawley male rats (N = 10-20/group) underwent transection of the sciatic and saphenous nerves unilaterally. Ralfinamide or its vehicle were administered per os for 7 days preoperatively (80 mg/kg; bid), followed by the vehicle or Ralfinamide, until postoperative d42. Autotomy was scored daily until d63. Lasting 'preemptive analgesia' was found in ats treated with ralfinamide preoperatively, expressed by delayed autotomy onset (P = 0.009) and reduced scores on d63 (P = 0.01). Rats treated with ralfinamide (30 or 60 mg/kg; bid) from the operation till d42, but not preoperatively, also showed delayed autotomy (P = 0.05, P = 0.001, respectively). Suppression of neuropathic pain-related behavior was likely caused by a combination of mechanisms reported for ralfinamide, including inhibition of Na+ and Ga++ currents in Nav1.3, Nav1.7. Nav1.8, and Cav2.2 channel in rat DRG neurons, inhibition of substance P release from spinal cord synaptosomes. NMDA receptor antagonism and neuroprotection. (C) 2008 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.