Muralidharan Arjun, Park Thomas S W, Mackie John T, Gimenez Luiz G S, Kuo Andy, Nicholson Janet R, Corradini Laura, Smith Maree T
Centre for Integrated Preclinical Drug Development, The University of Queensland, BrisbaneQLD, Australia.
School of Veterinary Science, The University of Queensland, GattonQLD, Australia.
Front Pharmacol. 2017 Jul 27;8:493. doi: 10.3389/fphar.2017.00493. eCollection 2017.
Chronic low back pain (LBP), the leading cause of disability globally, is notoriously difficult to treat. Most rodent models of LBP mimic lumbar radicular pain rather than mechanical LBP. Here, we describe establishment of a new rat model of mechanical LBP that is devoid of a neuropathic component. Groups of adult male Sprague Dawley rats were anesthetized and their lumbar L4/L5 and L5/L6 intervertebral disks (IVDs) were punctured (0.5 mm outer diameter, 2mm-deep) 5 (LPB-5X), or 10 (LBP-10X) times per disk. Sham-rats underwent similar surgery, but without disk puncture. Baseline noxious pressure hyperalgesia of lumbar axial deep tissues, mechanical allodynia in the hindpaws and gait were assessed prior to surgery and once-weekly until study completion on day 49. The model was also characterized using pharmacologic and histologic methods. Good animal health was maintained for ≥ 49 days post-surgery. For LBP- but not sham-rats, there was temporal development of noxious pressure hyperalgesia in lumbar axial deep tissues at days 14-49 post-surgery. Importantly, there were no between-group differences in von Frey paw withdrawal thresholds or gait parameters until study completion. On day 49, significant histologic changes were observed in the L4/L5 and L5/L6 IVDs for LBP-10X rats, but not sham-rats. In LBP-10X rats, single bolus doses of morphine produced dose-dependent relief of primary and secondary mechanical hyperalgesia in lumbar axial deep tissues at L4/L5 and L1, respectively. In conclusion, our new rat model has considerable potential for providing novel insight on the pathobiology of mechanical LBP and for analgesic efficacy assessment of novel compounds.
慢性下腰痛(LBP)是全球致残的主要原因,其治疗难度众所周知。大多数LBP啮齿动物模型模拟的是腰神经根性疼痛而非机械性LBP。在此,我们描述了一种无神经病变成分的新型机械性LBP大鼠模型的建立。将成年雄性Sprague Dawley大鼠分组麻醉,对其腰4/腰5和腰5/腰6椎间盘(IVD)进行穿刺(外径0.5毫米,深2毫米),每个椎间盘穿刺5次(LPB - 5X组)或10次(LBP - 10X组)。假手术组大鼠接受类似手术,但不进行椎间盘穿刺。在手术前以及每周一次直至第49天研究结束时,评估腰椎轴向深部组织的基线伤害性压力痛觉过敏、后爪机械性异常性疼痛和步态。还使用药理学和组织学方法对该模型进行了表征。术后≥49天内动物健康状况良好。对于LBP组而非假手术组大鼠,术后第14 - 49天腰椎轴向深部组织出现了伤害性压力痛觉过敏的时间性发展。重要的是,在研究结束前,两组之间在von Frey爪撤离阈值或步态参数方面没有差异。在第49天,观察到LBP - 10X组大鼠的腰4/腰5和腰5/腰6 IVD有明显的组织学变化,而假手术组大鼠则没有。在LBP - 10X组大鼠中,单次推注剂量的吗啡分别对腰4/腰5和腰1水平的腰椎轴向深部组织的原发性和继发性机械性痛觉过敏产生了剂量依赖性缓解。总之,我们的新型大鼠模型在为机械性LBP的病理生物学提供新见解以及评估新型化合物的镇痛效果方面具有很大潜力。