Sleep Division, Department of Neurology, Vanderbilt University Medical Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Norman Fixel Institute for Neurological Diseases, Department of Neurology, College of Medicine, University of Florida, Gainesville, FL 32610, USA.
Brain. 2024 Jan 4;147(1):26-38. doi: 10.1093/brain/awad283.
Restless legs syndrome (RLS) is responsive to opioid, dopaminergic and iron-based treatments. Receptor blocker studies in RLS patients suggest that the therapeutic efficacy of opioids is specific to the opioid receptor and mediated indirectly through the dopaminergic system. An RLS autopsy study reveals decreases in endogenous opioids, β-endorphin and perhaps Met-enkephalin in the thalamus of RLS patients. A total opioid receptor knock-out (mu, delta and kappa) and a mu-opioid receptor knock-out mouse model of RLS show circadian motor changes akin to RLS and, although both models show sensory changes, the mu-opioid receptor knock mouse shows circadian sensory changes closest to those seen in idiopathic RLS. Both models show changes in striatal dopamine, anaemia and low serum iron. However, only in the total receptor knock-out mouse do we see the decreases in serum ferritin that are normally found in RLS. There are also decreases in serum iron when wild-type mice are administered a mu-opioid receptor blocker. In addition, the mu-opioid receptor knock-out mouse also shows increases in striatal zinc paralleling similar changes in RLS. Adrenocorticotropic hormone and α-melanocyte stimulating hormone are derived from pro-opiomelanocortin as is β-endorphin. However, they cause RLS-like symptoms and periodic limb movements when injected intraventricularly into rats. These results collectively suggest that an endogenous opioid deficiency is pathogenetic to RLS and that an altered melanocortin system may be causal to RLS as well.
不宁腿综合征（RLS）对阿片类药物、多巴胺能和基于铁的治疗有反应。RLS 患者的受体阻滞剂研究表明，阿片类药物的治疗效果是特定于阿片受体的，并通过多巴胺能系统间接介导。一项 RLS 尸检研究表明，RLS 患者的丘脑内内源性阿片类物质、β-内啡肽和可能的 Met-脑啡肽减少。RLS 的总阿片受体敲除（mu、delta 和 kappa）和 mu 阿片受体敲除小鼠模型显示出类似于 RLS 的昼夜运动变化，尽管两种模型都显示出感觉变化，但 mu 阿片受体敲除小鼠显示出最接近特发性 RLS 所见的昼夜感觉变化。两种模型均显示纹状体多巴胺、贫血和血清铁低的变化。然而，只有在总受体敲除小鼠中，我们才会看到通常在 RLS 中发现的血清铁蛋白降低。当给予野生型小鼠 mu 阿片受体阻滞剂时，也会出现血清铁减少。此外，mu 阿片受体敲除小鼠还显示出纹状体锌的增加，与 RLS 中的类似变化平行。促肾上腺皮质激素和α-黑素细胞刺激素与β-内啡肽一样，是从前阿黑皮素原衍生而来的。然而，当它们被脑室注射到大鼠体内时，会引起类似于 RLS 的症状和周期性肢体运动。这些结果共同表明，内源性阿片类物质缺乏是 RLS 的发病机制，而黑素皮质素系统的改变也可能是 RLS 的原因。
