Chronic pain often predicts the onset of psychological distress. Symptoms including anxiety and depression after pain chronification reportedly are caused by brain remodeling/recruitment of the limbic and reward/aversion circuitries. Pain is the primary precipitating factor that has caused opioid overprescribing and continued overuse of opioids leading to the current opioid epidemic. Yet experimental pain therapies often fail in clinical trials. Better understanding of underlying pathologies contributing to pain chronification is needed to address these chronic pain related issues. In the present study, a chronic neuropathic pain model persisting 10 weeks was studied. The model develops both anxiety- and pain-related behavioral measures to mimic clinical pain. The manganese-enhanced magnetic resonance imaging (MEMRI) utilized improved MRI signal contrast in brain regions with higher neuronal activity in the rodent chronic constriction trigeminal nerve injury (CCI-ION) model. T1-weighted MEMRI signal intensity was increased compared to controls in supraspinal regions of the anxiety and aversion circuitry, including anterior cingulate gyrus (ACC), amygdala, habenula, caudate, and dorsomedial periaqueductal gray (PAG). Despite continuing mechanical hypersensitivity, MEMRI T1 signal intensity as the neuronal activity measure, was not significantly different in thalamus and decreased in somatosensory cortex (S1BF) of CCI-ION rats compared to naïve controls. This is consistent with decreased fMRI BOLD signal intensity in thalamus and cortex of patients with longstanding trigeminal neuropathic pain reportedly associated with grey matter volume decrease in these regions. Significant increase in MEMRI T2 signal intensity in thalamus of CCI-ION animals was indication of tissue water content, cell dysfunction and/or reactive astrogliosis. Decreased T2 signal intensity in S1BF cortex of rats with CCI-ION was similar to findings of reduced T2 signals in clinical patients with chronic orofacial pain indicating prolonged astrocyte activation. These findings support use of MEMRI and chronic rodent models for preclinical studies and therapeutic trials to reveal brain sites activated only after neuropathic pain has persisted in timeframes relevant to clinical pain and to observe treatment effects not possible in short-term models which do not have evidence of anxiety-like behaviors. Potential improvement is predicted in the success rate of preclinical drug trials in future studies with this model.

中文翻译：

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锰增强 MRI 揭示慢性神经性疼痛和焦虑样行为大鼠大脑焦虑和厌恶电路的变化

慢性疼痛通常预示着心理困扰的发作。据报道，疼痛慢性化后的包括焦虑和抑郁在内的症状是由边缘和奖赏/厌恶电路的大脑重塑/募集引起的。疼痛是导致阿片类药物过量处方和持续过度使用阿片类药物导致当前阿片类药物流行的主要诱因。然而，实验性疼痛疗法经常在临床试验中失败。需要更好地了解导致疼痛慢性化的潜在病理，以解决这些与慢性疼痛相关的问题。在本研究中，研究了持续 10 周的慢性神经性疼痛模型。该模型开发了焦虑和疼痛相关的行为测量来模拟临床疼痛。在啮齿动物慢性缩窄性三叉神经损伤 (CCI-ION) 模型中，锰增强磁共振成像 (MEMRI) 在具有较高神经元活动的大脑区域利用改进的 MRI 信号对比度。与对照组相比，T1 加权 MEMRI 信号强度在焦虑和厌恶电路的脊髓上区域增加，包括前扣带回 (ACC)、杏仁核、缰核、尾状核和背内侧导水管周围灰质 (PAG)。尽管机械超敏反应持续存在，但作为神经元活动测量的 MEMRI T1 信号强度在 CCI-ION 大鼠的丘脑中没有显着差异，并且在 CCI-ION 大鼠的体感皮层 (S1BF) 中与幼稚对照相比有所降低。这与据报道与这些区域灰质体积减少有关的长期三叉神经性疼痛患者的丘脑和皮质中 fMRI BOLD 信号强度降低是一致的。CCI-ION 动物丘脑中 MEMRI T2 信号强度的显着增加表明组织含水量、细胞功能障碍和/或反应性星形胶质细胞增生。CCI-ION 大鼠 S1BF 皮层 T2 信号强度降低与慢性口面部疼痛临床患者 T2 信号降低的结果相似，表明星形胶质细胞活化延长。这些发现支持使用 MEMRI 和慢性啮齿动物模型进行临床前研究和治疗试验，以揭示仅在与临床疼痛相关的时间范围内持续存在神经性疼痛后激活的大脑部位，并观察在没有证据的短期模型中不可能实现的治疗效果类似焦虑的行为。在未来使用该模型的研究中，预计临床前药物试验的成功率可能会有所提高。