Application of functional imaging techniques to animal models is vital to understand pain mechanisms, but is often confounded by the need to limit movement artefacts with anaesthesia, and a focus on evoked responses rather than clinically relevant spontaneous pain and related hyperalgesia. The aim of the present study was to investigate the potential of manganese-enhanced magnetic resonance imaging (MEMRI) to measure neural responses during on-going pain that underpins hyperalgesia in pre-clinical models of nociception. As a proof of concept that MEMRI is sensitive to the neural activity of spontaneous, intermittent behaviour, we studied a separate positive control group undergoing a voluntary running wheel experiment. In the pain models, pain behaviour (weight bearing asymmetry and hindpaw withdrawal thresholds (PWTs)) was measured at baseline and following either intra-articular injection of nerve growth factor (NGF, 10µg/50µl; acute pain model, n=4 rats per group), or the chondrocyte toxin monosodium iodoacetate (MIA, 1mg/50µl; chronic model, n=8 rats per group), or control injection. Separate groups of rats underwent a voluntary wheel running protocol (n=8 rats per group). Rats were administered with paramagnetic ion Mn2+ as soluble MnCl2 over seven days (subcutaneous osmotic pump) to allow cumulative activity-dependent neural accumulation in the models of pain, or over a period of running. T1-weighted MR imaging at 7T was performed under isoflurane anaesthesia using a receive-only rat head coil in combination with a 72mm volume coil for excitation. The pain models resulted in weight bearing asymmetry (NGF: 20.0 ± 5.2%, MIA: 15 ± 3%), and a reduction in PWT in the MIA model (8.3 ± 1.5g) on the final day of assessment before undergoing MR imaging. Voxel-wise and region-based analysis of MEMRI data did not identify group differences in T1 signal. However, MnCl2 accumulation in the VTA, right Ce amygdala, and left cingulate was negatively correlated with pain responses (greater differences in weight bearing), similarly MnCl2 accumulation was reduced in the VTA in line with hyperalgesia (lower PWTs), which suggests reduced regional activation as a result of the intensity and duration of pain experienced during the 7 days of MnCl2 exposure. Motor cortex T1-weighted signal increase was associated with the distance ran in the wheel running study, while no between group difference was seen. Our data suggest that on-going pain related signal changes identified using MEMRI offers a new window to study the neural underpinnings of spontaneous pain in rats.

译文

将功能成像技术应用于动物模型对于了解疼痛机制至关重要,但通常由于需要限制麻醉的运动伪影,并且关注诱发反应而不是临床相关的自发性疼痛和相关的痛觉过敏而感到困惑。本研究的目的是研究锰增强磁共振成像 (MEMRI) 在持续疼痛期间测量神经反应的潜力,这种疼痛是伤害感受的临床前模型中痛觉过敏的基础。为了证明MEMRI对自发的间歇性行为的神经活动敏感,我们研究了一个单独的阳性对照组,并进行了自愿的跑步轮实验。在疼痛模型中,在基线和关节内注射神经生长因子 (NGF,10 µ g/50 µ l; 急性疼痛模型,每组n = 4只大鼠) 后测量疼痛行为 (负重不对称和后爪戒断阈值 (PWTs)),或软骨细胞毒素碘乙酸单钠 (MIA,1mg/50 µ l; 慢性模型,每组n = 8只大鼠) 或对照注射。不同组的大鼠接受了自愿轮跑方案 (每组n = 8只大鼠)。在7天内 (皮下渗透泵) 给大鼠以顺磁性离子Mn2作为可溶性MnCl2,以允许在疼痛模型中或在一段时间内累积活动依赖性神经积累。在异氟醚麻醉下,使用仅接收的大鼠头线圈和72毫米体积线圈进行激发,在7t下进行T1-weighted MR成像。疼痛模型导致负重不对称 (NGF: 20.0 ± 5.2%,MIA: 15 ± 3%),并且在进行MR成像之前的评估的最后一天,MIA模型中的PWT降低 (8.3 ± 1.5g)。对MEMRI数据进行的体素分析和基于区域的分析未识别T1信号的组差异。然而,VTA,右Ce杏仁核和左扣带回中的MnCl2积累与疼痛反应呈负相关 (负重差异更大),类似地,VTA中的MnCl2积累与痛觉过敏 (较低的PWTs) 相一致,这表明由于MnCl2暴露7天期间经历的疼痛强度和持续时间导致区域激活减少。在车轮运行研究中,运动皮层T1-weighted信号的增加与行驶距离有关,而组之间没有差异。我们的数据表明,使用MEMRI识别出的与疼痛相关的持续信号变化为研究大鼠自发性疼痛的神经基础提供了新的窗口。

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