Department of Anesthesiology, University of Texas Medical Branch, Galveston, TX, USA.
J Pain Res. 2012;5:415-24. doi: 10.2147/JPR.S34977. Epub 2012 Oct 25.
Evaluation of analgesics in large animals is a necessary step in the development of better pain medications or gene therapy prior to clinical trials. However, chronic neuropathic pain models in large animals are limited. To address this deficiency, we developed a neuropathic pain model in sheep, which shares many anatomical similarities in spine dimensions and cerebrospinal fluid volume as humans.
A neuropathic pain state was induced in sheep by tight ligation and axotomy of the common peroneal nerve. The analgesic effect of intrathecal (IT) morphine was investigated. Interspecies comparison was conducted by analyzing the ceiling doses of IT morphine for humans, sheep, and rats.
Peroneal nerve injury (PNI) produced an 86% decrease in von-Frey filament-evoked withdrawal threshold on postsurgery day 3 and the decrease lasted for the 8-week test period. Compared to the pre-injury, sham, and contralateral hindlimb, the IT morphine dose that produces 50% of maximum analgesia (ED(50)) for injured PNI hindlimb was 1.8-fold larger and E(max), the dose that produces maximal analgesia, was 6.1-fold lower. The sheep model closely predicts human IT morphine ceiling dose by allometric scaling. This is in contrast to the approximately 10-fold lower morphine ceiling dose predicted by the rat spinal nerve ligated or spared nerve injury models.
PNI sheep model has a fast onset and shows stable and long-lasting pain behavioral characteristics. Since the antinociceptive properties of IT morphine are similar to those observed in humans, the PNI sheep model will be a useful tool for the development of analgesics. Its large size and consistent chronic pain behavior will facilitate the development and evaluation of surgical intervention and gene therapy. The PNI sheep pain model provides us with the opportunity for multi-species testing, which will improve the success of clinical trials.
在临床试验之前，为了开发更好的疼痛药物或基因治疗方法，有必要对大型动物的镇痛剂进行评估。然而，大型动物的慢性神经性疼痛模型有限。为了解决这一不足，我们建立了绵羊神经性疼痛模型，该模型在脊柱尺寸和脑脊液量方面与人有许多相似之处。
通过对坐骨神经的紧密结扎和轴索切断，在绵羊中诱发神经性疼痛状态。研究了鞘内（IT）吗啡的镇痛作用。通过分析人类、绵羊和大鼠的 IT 吗啡天花板剂量，进行了种间比较。
腓总神经损伤（PNI）导致术后第 3 天 Von-Frey 纤维诱发的退缩阈值下降 86%，并且这种下降持续了 8 周的测试期。与术前、假手术和对侧后肢相比，产生受伤 PNI 后肢 50%最大镇痛作用的 IT 吗啡剂量（ED（50））增加了 1.8 倍，产生最大镇痛作用的 E（max）剂量降低了 6.1 倍。绵羊模型通过比例缩放法非常准确地预测了人类 IT 吗啡的天花板剂量。与之形成对比的是，通过结扎或保留大鼠脊神经的模型预测的吗啡天花板剂量大约低 10 倍。
PNI 绵羊模型具有快速发作的特点，并表现出稳定而持久的疼痛行为特征。由于 IT 吗啡的镇痛特性与在人类中观察到的相似，因此 PNI 绵羊模型将成为开发镇痛药的有用工具。它的体型较大且慢性疼痛行为一致，将有助于手术干预和基因治疗的开发和评估。PNI 绵羊疼痛模型为我们提供了多物种测试的机会，这将提高临床试验的成功率。
