Division of Clinical and Laboratory Investigation, Brighton and Sussex Medical School, Medical Research Building, University of Sussex, Falmer, Brighton BN1 9PS, United Kingdom.
Neuroscience. 2013 Mar 13;233:174-83. doi: 10.1016/j.neuroscience.2012.12.022. Epub 2012 Dec 20.
Studies on the neuritis model suggest that in many patients with neuropathic pain, symptoms may be due to nerve inflammation rather than frank nerve injury. Treatments for these patients are often ineffective. The neuroprotective and hematopoietic agent erythropoietin (EPO) has been shown to reverse pain behaviors in nerve injury models and therefore may be of therapeutic benefit. However, EPO can cause thrombosis. ARA290 is an analog of EPO that has the neuroprotective activities of EPO without stimulating hematopoiesis. The present study has examined the effects of ARA290 on pain behavior in the neuritis model. Following neuritis induction, 30 or 120 μg/kg ARA290 or saline vehicle was injected intraperitoneally into rats daily from day 1 post surgery. Animals were assessed for mechanical allodynia and heat hyperalgesia. Levels of the cytokine tumor necrosis factor-α (TNF-α) and chemokine (CC motif) ligand 2 (CCL2) mRNA were also assessed using polymerase chain reaction. Vehicle-treated neuritis animals (n=20) developed signs of mechanical allodynia and heat hyperalgesia that reached a maximum on day 4 and 3 of testing, respectively. Treatment with either 30 (n=11) or 120 μg/kg ARA290 (n=9) prevented the development of mechanical allodynia. However, ARA290 did not significantly affect heat hyperalgesia. There was no significant difference between the effects of each drug dose (p<0.05, unpaired t test comparing area under the curve for mechanical allodynia). The levels of CCL2 and TNF-α mRNA in the nerve and Gelfoam were not significantly different following 120 μg/kg ARA290 treatment (n=3-7) compared to vehicle-treated animals (n=3-7; p=0.24; unpaired t tests). In summary, ARA290 may be beneficial in the treatment of neuropathic pain symptoms where signs of nerve injury are absent on clinical assessment. The mechanisms of action do not appear to involve the inhibition of TNF-α or CCL2 production.
神经炎模型的研究表明，在许多患有神经性疼痛的患者中，症状可能是由于神经炎症而非明显的神经损伤引起的。这些患者的治疗往往无效。神经保护和造血剂促红细胞生成素（EPO）已被证明可逆转神经损伤模型中的疼痛行为，因此可能具有治疗益处。然而，EPO 会引起血栓形成。ARA290 是 EPO 的类似物，具有 EPO 的神经保护活性而不刺激造血。本研究检查了 ARA290 对神经炎模型中疼痛行为的影响。神经炎诱导后，30 或 120μg/kg ARA290 或生理盐水载体每天腹膜内注射至手术后第 1 天。对动物进行机械性痛觉过敏和热痛觉过敏评估。还使用聚合酶链反应评估细胞因子肿瘤坏死因子-α（TNF-α）和趋化因子（CC 基序）配体 2（CCL2）mRNA 的水平。用载体处理的神经炎动物（n=20）出现机械性痛觉过敏和热痛觉过敏的迹象，分别在测试的第 4 天和第 3 天达到最大值。用 30μg/kg（n=11）或 120μg/kg ARA290（n=9）治疗可预防机械性痛觉过敏的发展。然而，ARA290 对热痛觉过敏没有显著影响。两种药物剂量的作用之间没有显着差异（p<0.05，未配对 t 检验比较机械性痛觉过敏的曲线下面积）。与载体处理的动物（n=3-7；p=0.24；未配对 t 检验）相比，用 120μg/kg ARA290 处理后神经和 Gelfoam 中的 CCL2 和 TNF-α mRNA 水平没有显着差异（n=3-7；p=0.24；未配对 t 检验）。总之，在临床评估不存在神经损伤迹象的情况下，ARA290 可能对治疗神经性疼痛症状有益。作用机制似乎不涉及抑制 TNF-α 或 CCL2 的产生。
