Attenuation of morphine tolerance by minocycline and pentoxifylline in naive and neuropathic mice
Attenuation of morphine tolerance by minocycline and pentoxifylline in naive and neuropathic mice
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DOI：
10.1016/j.bbi.2008.07.005
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发表时间：
2009-01-01
影响因子：
15.1
通讯作者：
Przewlocka, Barbara
中科院分区：
文献类型：
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作者：
Mika, Joanna;Wawrzczak-Bargiela, Agnieszka;Przewlocka, Barbara
我们之前已经证明，神经胶质抑制剂可以减少异常性疼痛和痛觉过敏的发生，增强单剂量吗啡在神经性疼痛模型中的作用。本研究探讨了两种胶质细胞激活抑制剂米诺环素和己酮可可碱对幼稚和慢性缩窄性损伤 (CCI) 暴露小鼠吗啡耐受性发展的影响。首次注射吗啡（20 mg/kg；腹腔注射）和 CCI 暴露小鼠（40 mg/kg；腹腔注射）每日两次，6 天后可耐受其抗伤害作用。吗啡注射与米诺环素（30 mg/kg，腹腔注射）或己酮可可碱（20mg/kg，腹腔注射）联合注射，在第一次吗啡注射前预先注射两次在 CCI 暴露小鼠中首次给药或受伤前给药，每天重复两次，每次吗啡给药前 30 分钟。通过治疗，吗啡耐受性的发展延迟了 5 天（从 6 天到 11 天），这是通过对幼稚小鼠的甩尾试验和对 CCI 暴露小鼠的甩尾、冯弗雷和冷板试验进行测量的。 CD11b/c 和 GFAP 蛋白的蛋白质印迹分析表明，米诺环素和己酮可可碱在延迟吗啡镇痛耐受性发展的剂量下，显着减少吗啡诱导的 CD11b/c 蛋白水平的增加。我们发现，在正常和神经病理性疼痛条件下，重复全身施用神经胶质抑制剂可通过减弱这种小胶质细胞标志物的水平来显着延迟吗啡耐受性的发展。我们的结果支持这样的观点：在吗啡治疗/治疗过程中靶向小胶质细胞激活是一种新颖且有临床前景的方法，可增强吗啡的镇痛效果，特别是在神经性疼痛中。 (c) 2008 Elsevier Inc. 保留所有权利。
We have previously demonstrated that glial inhibitors reduce the development of allodynia and hyperalgesia, potentiating the effect of a single-morphine dose in a neuropathic pain model. This-study explores the effects of two glial activation inhibitors,minocycline and pentoxifylline, on the development of tolerance to morphine in naive and chronic constriction injury (CCI)-exposed mice. Administration of morphine to naive (20 mg/kg; i.p.) and CCI-exposed mice (40 mg/kg; i.p.) twice daily resulted in tolerance to its anti-nociceptive effect after 6 days., Injections of morphine were combined with minocycline (30 mg/kg, i.p.) or pentoxifylline (20mg/kg, i.p.) administered as two preemptive doses before first morphine administration in naive or pre-injury in CCI-exposed mice, and repeated twice daily 30 min before each morphine administration. With treatment, development of morphine tolerance was delayed by 5 days (from 6 to 11 days), as measured by the tail-flick test in naive and by tail-flick, von Frey, and cold plate,tests in CCI-exposed mice. Western blot analysis of CD11b/c and GFAP protein demonstrated that minocycline and pentoxifylline, at doses delaying development of tolerance to morphine analgesia, significantly diminished the morphine-induced increase in CD11b/c protein level. We found that repeated systemic administration of glial inhibitors significantly delays development of morphine tolerance by attenuating the level of this microglial marker under normal and neuropathic pain conditions. Our results support the idea that targeting microglial activation during morphine therapy/treatment is a novel and clinically promising method for enhancing morphine's analgesic effects, especially in neuropathic pain.. (c) 2008 Elsevier Inc. All rights reserved.