Department of Neurosurgery, Yonsei University College of Medicine, Seoul, South Korea.
Brain Korea 21 PLUS Project for Medical Science and Brain Research Institute, Yonsei University College of Medicine, Seoul, Korea.
Eur J Pain. 2018 Oct;22(9):1691-1700. doi: 10.1002/ejp.1254. Epub 2018 Jul 2.
Neuropathic pain is associated with abnormal sensitivity of the central nervous system. Although the mechanism underlying the development of sensitization remains to be fully elucidated, recent studies have reported that neuroplastic changes in the pain circuitry may be involved in hypersensitivity associated with neuropathic pain. However, it is difficult to investigate such phenomena in existing animal pain model. Therefore, in this study, we developed a novel animal model - the circuit plasticity reconstruction (CPR) model - to mimic central sensitization associated with neuroplastic changes.
NMDA and Ro 25-6981 were injected into the right insular cortex of Sprague-Dawley rats, while electrical stimulation was delivered to the contralateral hind paw. Mechanical allodynia was tested by von Frey test with up-down method, and neuroplastic changes were confirmed by PSA-NCAM-positive immunostaining.
The mechanical withdrawal threshold of the left hind paw decreased beginning 1 day after CPR modelling and persisted until day 21 comparing to the modified CPR 1 (mod-CPR 1) group (CPR: 91.68 ± 1.8%, mod-CPR 1: 42.71 ± 3.4%, p < 0.001). In contrast, mod-CPR 2 surgery without electrical stimulation did not induce mechanical allodynia. Immunostaining for PSA-NCAM also revealed that neuroplastic changes had occurred in the CPR group.
Our results demonstrated that CPR modelling induced neuroplasticity within the insular cortex, leading to alterations in the neural circuitry and central sensitization.
This article represents that the CPR model can mimic the neuropathic pain derived by neuroplastic changes. Our findings indicate that the CPR model may aid the development of novel therapeutic strategies for neuropathic pain and in elucidating the mechanisms underlying pain induced by central sensitization and neuroplastic changes.
神经性疼痛与中枢神经系统的异常敏感有关。尽管导致敏化的机制尚未完全阐明，但最近的研究报告称，疼痛回路中的神经可塑性变化可能与神经性疼痛相关的超敏反应有关。然而，在现有的动物疼痛模型中，很难研究这种现象。因此，在本研究中，我们开发了一种新的动物模型——回路可塑性重建（CPR）模型——来模拟与神经可塑性变化相关的中枢敏化。
NMDA 和 Ro 25-6981 被注射到 Sprague-Dawley 大鼠的右侧岛叶皮层，同时对对侧后足进行电刺激。采用von Frey 测试上下法检测机械性痛觉过敏，并用 PSA-NCAM 阳性免疫染色证实神经可塑性变化。
CPR 模型建立后 1 天，左后爪的机械退缩阈值开始下降，并持续至第 21 天，与改良 CPR 1（mod-CPR 1）组相比（CPR：91.68±1.8%，mod-CPR 1：42.71±3.4%，p<0.001）。相比之下，没有电刺激的 mod-CPR 2 手术不会引起机械性痛觉过敏。PSA-NCAM 的免疫染色也表明，CPR 组发生了神经可塑性变化。
我们的结果表明，CPR 模型诱导了岛叶皮层内的神经可塑性，导致了神经回路的改变和中枢敏化。
本文代表了 CPR 模型可以模拟由神经可塑性变化引起的神经性疼痛。我们的发现表明，CPR 模型可能有助于开发治疗神经性疼痛的新策略，并阐明中枢敏化和神经可塑性变化引起疼痛的机制。
