Department of Clinical Neurophysiology, University Medical Centre Göttingen, 37075 Göttingen, Germany.
J Neurosci. 2011 Jan 5;31(1):70-7. doi: 10.1523/JNEUROSCI.0959-10.2011.
Restless legs syndrome (RLS) is a common neurological disorder whose exact pathophysiological mechanism remains unclear despite the successful use of dopaminergic treatment and recent discovery of predisposing genetic factors. As iron deficiency has been associated with RLS for some patients and there is evidence for decreased spinal dopamine D(3)-receptor (D3R) signaling in RLS, we aimed at establishing whether D3R activity and iron deficiency share common pathways within the pathophysiology of RLS sensory and motor symptoms. Using a combined mouse model of iron deficiency and dopamine D(3)-receptor deficiency (D3R-/-), circadian motor symptoms were evaluated by continuous recording of spontaneous wheel running activity. Testing the acute and persistent pain responses with the hot-plate test and formalin test, respectively, assessed sensory symptoms. A 15 week iron-deficient (ID) diet alone increased acute and persistent pain responses as compared to control diet. As compared to C57BL/6 (WT), homozygous D3R-/- mice already exhibited elevated responses to acute and persistent pain stimuli, where the latter was further elevated by concurrent iron deficiency. ID changed the circadian activity pattern toward an increased running wheel usage before the resting period, which resembled the RLS symptom of restlessness before sleep. Interestingly, D3R-/- shifted this effect of iron deficiency to a time point 3-4 h earlier. The results confirm the ability of iron deficiency and D3R-/- to evoke sensory and motor symptoms in mice resembling those observed in RLS patients. Furthermore this study suggests an increase of ID-related sensory symptoms and modification of ID-related motor symptoms by D3R-/-.
不宁腿综合征（RLS）是一种常见的神经系统疾病，尽管多巴胺能治疗成功和最近发现易患遗传因素，但确切的病理生理机制仍不清楚。由于一些患者的 RLS 与铁缺乏有关，并且有证据表明 RLS 中脊髓多巴胺 D3 受体（D3R）信号降低，我们旨在确定 D3R 活性和铁缺乏是否在 RLS 感觉和运动症状的病理生理学中具有共同途径。使用铁缺乏和多巴胺 D3 受体缺乏（D3R-/-）的小鼠模型，通过连续记录自发轮跑活动评估昼夜运动症状。使用热板试验和福尔马林试验分别测试急性和持续性疼痛反应，评估感觉症状。与对照饮食相比，15 周的缺铁（ID）饮食单独增加了急性和持续性疼痛反应。与 C57BL/6（WT）相比，纯合 D3R-/- 小鼠已经对急性和持续性疼痛刺激表现出升高的反应，而后者在同时发生铁缺乏时进一步升高。ID 改变了昼夜活动模式，在休息期前增加了跑轮使用量，这类似于 RLS 患者睡眠前的不安症状。有趣的是，D3R-/- 将这种缺铁效应提前了 3-4 小时。结果证实了铁缺乏和 D3R-/- 诱发类似于 RLS 患者观察到的感觉和运动症状的能力。此外，这项研究表明 ID 相关的感觉症状增加和 D3R-/- 对 ID 相关运动症状的修饰。
