Systemic Administration of Propentofylline, Ibudilast, and (+)-Naltrexone Each Reverses Mechanical Allodynia in a Novel Rat Model of Central Neuropathic Pain
Systemic Administration of Propentofylline, Ibudilast, and (+)-Naltrexone Each Reverses Mechanical Allodynia in a Novel Rat Model of Central Neuropathic Pain
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DOI：
10.1016/j.jpain.2013.12.007
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发表时间：
2014-04-01
期刊：
影响因子：
4
通讯作者：
Watkins, Linda R.
中科院分区：
文献类型：
--
作者：
Ellis, Amanda;Wieseler, Julie;Watkins, Linda R.
中枢神经性疼痛（CNP）是中枢神经系统损伤的衰弱后果，目前的治疗无效。为了探索CNP的机制，我们建立了大鼠T13/L1背根撕脱伤模型。由此产生的背角损伤造成双侧水平以下（L4-L6）机械异常性痛。这种异常性疼痛，称为脊髓神经性撕脱性疼痛，发生在没有混杂性麻痹的情况下。为了确定该模型的特征，我们进行了一系列研究，旨在确定脊髓神经性撕脱性疼痛是否可以通过3种假定的神经胶质激活抑制剂中的任何一种来逆转，每种抑制剂都有不同的作用机制。事实上，磷酸二酯酶抑制剂丙烯茶碱、巨噬细胞迁移抑制因子抑制剂伊布司特和toll样受体4拮抗剂(+)-纳曲酮均能在双侧逆转低于水平的异位性疼痛。引人注目的是，这些药物在第一次给药时都没有影响脊柱神经性撕脱性疼痛，但在获得疼痛逆转之前需要每天给药1至2周。考虑到这些神经胶质调节剂都能逆转CNP，这些结果表明，神经胶质有助于维持这种疼痛，持久释放巨噬细胞迁移抑制因子和内源性toll样受体4激动剂对维持CNP很重要。所有3种神经胶质调节药物的疗效明显延迟，可能有助于解释较短剂量方案后明显的药物失败。观点：创伤后发生的CNP通常被患者描述为严重和无法忍受。不幸的是，目前的治疗方法并不有效。这项工作表明，使用靶向神经胶质细胞的药物治疗可能是CNP的有效临床治疗方法。(C) 2014年由美国疼痛学会出版。Elsevier Inc.出版。版权所有
Central neuropathic pain (CNP) is a debilitating consequence of central nervous system damage for which current treatments are ineffective. To explore mechanisms underlying CNP, we developed a rat model involving T13/L1 dorsal root avulsion. The resultant dorsal horn damage creates bilateral below-level (L4-L6) mechanical allodynia. This allodynia, termed spinal neuropathic avulsion pain, occurs in the absence of confounding paralysis. To characterize this model, we undertook a series of studies aimed at defining whether spinal neuropathic avulsion pain could be reversed by any of 3 putative glial activation inhibitors, each with distinct mechanisms of action. Indeed, the phosphodiesterase inhibitor propentofylline, the macrophage migration inhibitory factor inhibitor ibudilast, and the toll-like receptor 4 antagonist (+)-naltrexone each reversed below-level allodynia bilaterally. Strikingly, none of these impacted spinal neuropathic avulsion pain upon first administration but required 1 to 2 weeks of daily administration before pain reversal was obtained. Given reversal of CNP by each of these glial modulatory agents, these results suggest that glia contribute to the maintenance of such pain and enduring release of macrophage migration inhibitory factor and endogenous agonists of toll-like receptor 4 is important for sustaining CNP. The markedly delayed efficacy of all 3 glial modulatory drugs may prove instructive for interpretation of apparent drug failures after shorter dosing regimens.Perspective: CNP that develops after trauma is often described by patients as severe and intolerable. Unfortunately, current treatments are not effective. This work suggests that using pharmacologic treatments that target glial cells could be an effective clinical treatment for CNP. (C) 2014 by the American Pain Society. Published by Elsevier Inc. All rights reserved