Cannabinoid agonist WIN 55,212-2 prevents the development of paclitaxel-induced peripheral neuropathy in rats. Possible involvement of spinal glial cells
Cannabinoid agonist WIN 55,212-2 prevents the development of paclitaxel-induced peripheral neuropathy in rats. Possible involvement of spinal glial cells
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DOI：
10.1016/j.ejphar.2012.02.008
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发表时间：
2012-05-05
影响因子：
5
通讯作者：
Goicoechea, Carlos
中科院分区：
文献类型：
--
作者：
Burgos, Elisa;Gomez-Nicola, Diego;Goicoechea, Carlos
脊髓神经胶质细胞的激活有助于慢性疼痛状态的发展和维持，包括各种原因的神经病理性疼痛。大麻素类化合物已在多种神经病理性疼痛模型中显示出抗伤害性作用，并有望成为治疗神经病理性疼痛的一类药物。因此，在紫杉醇诱导的周围神经病变的整个发展过程中，重复使用合成大麻素激动剂Win 55,212-2的效果被检测。雄性Wistar大鼠腹腔注射诱发痛性神经病变。紫杉醇(1 mg/kg)隔日给药。紫杉醇处理组动物腹腔注射Win 55,212-2(1 mg/kg)。或米诺环素(15 mg/kg，ip)，一种小胶质细胞抑制剂，连续14天，与抗肿瘤药物同时服用。在首次给药后第1、7、14、21和28天评估过敏行为的发展。同时测定第29天小胶质细胞和星形胶质细胞的激活情况以及脊髓内促炎细胞因子释放的时间进程。与米诺环素类似，重复给予Win 55,212-2可防止紫杉醇处理的大鼠出现热痛敏和机械性痛觉异常。Win 55,212-2治疗还可在第29天阻止紫杉醇诱导的脊髓小胶质细胞和星形胶质细胞的激活，并减少早期脊髓促炎细胞因子(IL-1β、IL-6和肿瘤坏死因子(TNF)-α)的产生。我们的结果证实了在紫杉醇诱导的周围神经病发展过程中胶质细胞反应性的变化，并支持Win 55,212-2可能通过胶质细胞反应性失活对这种神经病的发展起到预防作用。(C)2012爱思唯尔B.V.保留所有权利。
Spinal glial activation contributes to the development and maintenance of chronic pain states, including neuropathic pain of diverse etiologies. Cannabinoid compounds have shown antinociceptive properties in a variety of neuropathic pain models and are emerging as a promising class of drugs to treat neuropathic pain. Thus, the effects of repeated treatment with WIN 55,212-2, a synthetic cannabinoid agonist, were examined throughout the development of paclitaxel-induced peripheral neuropathy. Painful neuropathy was induced in male Wistar rats by intraperitoneal (i.p.) administration of paclitaxel (1 mg/kg) on four alternate days. Paclitaxel-treated animals received WIN 55,212-2 (1 mg/kg, i.p.) or minocycline (15 mg/kg, i.p.), a microglial inhibitor, daily for 14 days, simultaneous with the antineoplastic. The development of hypersensitive behaviors was assessed on days 1, 7, 14,21 and 28 following the initial administration of drugs. Both the activation of glial cells (microglia and astrocytes) at day 29 and the time course of proinflammatory cytokine release within the spinal cord were also determined. Similar to minocycline, repeated administration of WIN 55,212-2 prevented the development of thermal hyperalgesia and mechanical allodynia in paclitaxel-treated rats. WIN 55,212-2 treatment also prevented spinal microglial and astrocytic activation evoked by paclitaxel at day 29 and attenuated the early production of spinal proinflammatoty cytokines (interleukin (IL)-1 beta, IL-6 and tumor necrosis factor (TNF)-alpha). Our results confirm changes in the reactivity of glial cells during the development of peripheral neuropathy induced by paclitaxel and support a preventive effect of WIN 55,212-2, probably via glial cells reactivity inactivation, on the development of this neuropathy. (C) 2012 Elsevier B.V. All rights reserved.