An IL-1 receptor antagonist blocks a morphine-induced attenuation of locomotor recovery after spinal cord injury.
An IL-1 receptor antagonist blocks a morphine-induced attenuation of locomotor recovery after spinal cord injury.
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IL-1受体拮抗剂阻止了吗啡诱导的脊髓损伤后运动恢复的衰减。
DOI：
10.1016/j.bbi.2010.10.018
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发表时间：
2011-02
影响因子：
15.1
通讯作者：
Grau, James W.
中科院分区：
文献类型：
--
作者：
Hook, Michelle A.;Washburn, Stephanie N.;Moreno, Georgina;Woller, Sarah A.;Puga, Denise;Lee, Kuan H.;Grau, James W.
吗啡是治疗脊髓损伤后慢性疼痛最常用的处方药之一。然而，尽管吗啡被广泛使用，人们对脊髓损伤后使用吗啡的次要后果知之甚少。不幸的是，我们之前的研究表明，在中度脊髓挫伤的急性期单次注射吗啡，显著削弱运动功能，减少体重增加，并产生矛盾疼痛的症状。目前的研究集中在调节这些影响的细胞机制上。基于其他模型的数据，我们假设促炎细胞因子可能在吗啡诱导的功能减弱中发挥作用。实验1证实，挫伤后1d全身注射吗啡(20 mg/kg)可显著增加伤后24小时脊髓IL-1β的表达水平。实验2扩展了这些发现，表明单剂量吗啡(90微克，I.T.)脊髓直接给药后30min和24小时脊髓IL-1β的表达水平均升高。实验3表明，白介素1受体拮抗剂(IL-1ra，I.T.)鞘内注射吗啡(90微克)前，可阻断吗啡对运动恢复的不良影响。此外，预先给予3微克IL-1ra可阻止28天后单独使用吗啡组观察到的神经病理性疼痛症状的增加。然而，IL-1ra也有不依赖于吗啡的副作用。单独使用IL-1ra治疗破坏了运动功能的恢复，加强了体重减轻，并显著增加了损伤部位的组织丢失。总体而言，这些数据表明，吗啡破坏了脊髓中促炎症细胞因子浓度的关键平衡，这破坏了功能的恢复。
Morphine is one of the most commonly prescribed medications for the treatment of chronic pain after a spinal cord injury (SCI). Despite widespread use, however, little is known about the secondary consequences of morphine use after SCI. Unfortunately, our previous studies show that administration of a single dose of morphine, in the acute phase of a moderate spinal contusion injury, significantly attenuates locomotor function, reduces weight gain, and produces symptoms of paradoxical pain. The current study focused on the cellular mechanisms that mediate these effects. Based on data from other models, we hypothesized that pro-inflammatory cytokines might play a role in the morphine-induced attenuation of function. Experiment 1 confirmed that systemic morphine (20 mg/kg) administered one day after a contusion injury significantly increased expression levels of spinal IL-1β 24 hrs later. Experiment 2 extended these findings, demonstrating that a single dose of morphine (90 µg, i.t.) applied directly onto the spinal cord increased expression levels of spinal IL-1β at both 30 min and 24 hrs after administration. Experiment 3 showed that administration of an interleukin-1 receptor antagonist (IL-1ra, i.t.) prior to intrathecal morphine (90 µg), blocked the adverse effects of morphine on locomotor recovery. Further, pre-treatment with 3 µg IL-1ra prevented the increased expression of at-level neuropathic pain symptoms that was observed 28 days later in the group treated with morphine-alone. However, the IL-1ra also had adverse effects that were independent of morphine. Treatment with the IL-1ra alone undermined recovery of locomotor function, potentiated weight loss and significantly increased tissue loss at the injury site. Overall, these data suggest that morphine disrupts a critical balance in concentrations of pro-inflammatory cytokines in the spinal cord, and this undermines recovery of function.
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