Ethosuximide reverses paclitaxel- and vincristine-induced painful peripheral neuropathy
Ethosuximide reverses paclitaxel- and vincristine-induced painful peripheral neuropathy
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DOI：
10.1016/j.pain.2004.01.029
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发表时间：
2004-05-01
期刊：
影响因子：
7.4
通讯作者：
Bennett, GJ
中科院分区：
文献类型：
--
作者：
Flatters, SJL;Bennett, GJ
紫杉醇(Taxol(R))是治疗实体瘤最有效和最常用的化疗药物之一。然而，紫杉醇会产生外周神经毒性，患者报告在紫杉醇治疗期间和之后经常会出现感觉异常和神经病理性疼痛。这种剂量限制副作用的潜在机制目前尚不清楚，也没有有效的药物来预防或控制它。雄性SD大鼠接受4次腹腔注射。隔日注射紫杉醇2 mg/kg。使用von Frey细丝和丙酮进行的行为评估表明，这种紫杉醇治疗导致了明显的机械性和冷痛敏/痛敏。因此，这些研究旨在测试潜在的止痛剂对已建立的紫杉醇诱导的疼痛。紫杉醇诱导的疼痛似乎对阿片类药物治疗相对耐受。4 mg/kg吗啡无效，ip。8 mg/kg吗啡仅能逆转50%的机械性痛觉过敏/痛觉过敏。有趣的是，最大耐受量(I.P.0.2 mg/ka的NMDA受体拮抗剂MK-801对机械性痛觉过敏/痛觉过敏无明显逆转作用，提示NMDA受体在紫杉醇诱导的疼痛中作用不大。乙硫胺(I.P.)450 mg/kg)抗癫痫和相对选择性的T型钙通道阻滞剂可几乎完全逆转机械性痛觉过敏/痛觉过敏。乙硫胺重复给药(I.P.每天100或300 mg/kg，连续3天)显示与剂量相关的机械性痛敏/痛觉过敏的一致逆转，但没有耐受性的证据。乙硫胺(I.P.)300 mg/kg还能逆转紫杉醇诱导的冷超敏和长春新碱诱导的机械性超敏/痛敏。这些数据表明，T型钙通道可能在化疗引起的神经病变中发挥作用，并确认乙琥胺是一种新的治疗化疗引起的疼痛的潜在药物。(C)2004年国际疼痛研究协会。爱思唯尔出版，版权所有。
Paclitaxel (Taxol(R)) is one of the most effective and frequently used chemotherapeutics for the treatment of solid turnours. However, paclitaxel produces peripheral neurotoxicity with patients reporting sensory abnormalities and neuropathic pain during and often persisting after paclitaxel therapy. The mechanisms underlying this dose-limiting side effect are Currently unknown and there are no validated drugs for its prevention or control. Male Sprague-Dawley rats received four intraperitoneal (i.p.) injections on alternate days of 2 mg/kg paclitaxel. Behavioural assessment using von Frey filaments and acetone showed that such paclitaxel treatment induced a pronounced mechanical and cold allodynia/hyperalgesia. Thus these studies aim to test potential analgesics on established paclitaxel-induced pain. Paclitaxel-induced pain appears to be relatively resistant to opioid therapy i.p. 4 mg/kg morphine was ineffective and i.p. 8 mg/kg morphine only elicited up to a 50% reversal of mechanical allodynia/hyperalgesia. Interestingly, a maximally tolerated dose (i.p. 0.2 mg/ka) of the potent NMDA receptor antagonist MK-801 produced no significant reversal of the mechanical allodynia/hyperalgesia suggesting that NMDA receptors have little role in paclitaxel-induced pain. Ethosuximide (i.p. 450 mg/kg) an anti-epileptic and relatively selective T-type calcium channel blocker elicited a near complete reversal of mechanical allodynia/hyperalgesia. Repetitive dosing with ethosuximide (i.p. 100 or 300 mg/kg daily for 3 days) showed a dose-related consistent reversal of mechanical allodynia/hyperalgesia with no evidence of tolerance. Ethosuximide (i.p. 300 mg/kg) also reversed paclitaxel-induced cold allodynia and vincristine-induced mechanical allodynia/hyperalgesia. These data Suggest that T-type calcium channels may play a role in chemotherapy-induced neuropathy and moreover identify ethosuximide as a new potential for chemotherapy-induced pain. (C) 2004 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.