Walters Arthur S, Ondo William G, Zhu Wen, Le Weidong
Department of Neurology, Vanderbilt University Medical Center, Nashville, TN 37232-2551, USA.
J Neurol Sci. 2009 Apr 15;279(1-2):62-5. doi: 10.1016/j.jns.2008.12.022. Epub 2009 Jan 23.
Opioids are an effective treatment for the signs and symptoms of Restless Legs Syndrome (RLS) and the signs and symptoms of RLS return when the opiate receptor blocker naloxone is given to opioid treated RLS patients in a blinded fashion. These data suggest that the opioid effect is specific to the opiate receptor in RLS and implicate the endogenous opioid system with its enkephalins and endorphins in the pathogenesis of RLS. We therefore measured Beta endorphin, Met-enkephalin and Leu-enkephalin levels in thalamus and substantia nigra of RLS patients (5 F - avg age 80.2 years) compared to controls (5 F, 1 M - avg age 76.3 years). One half of each brain was fixed in paraformaldehyde (PFA) in phosphate buffered saline (PBS) for pathologic evaluation and paraffin sections were stained with antibodies. Cell numbers were counted in a blinded fashion. In the thalamus, there were reductions of Beta-endorphin and Met-enkephalin positive cells by 37.5% (p=.006, effect size 2.16) and 26.4% (p=.028, effect size 1.58), respectively, in RLS patients compared to controls. There was no difference in Leu-enkephalin in the thalamus or changes in Beta endorphin, Met-enkephalin, Leu-enkephalin or Tyrosine Hydroxylase, the rate limiting step for dopamine synthesis, in the substantia nigra. Although one of the main hypotheses for pathogenesis has been that there is a dopaminergic hypofunction in RLS, this lack of decrease in Tyrosine Hydroxylase in substantia nigra is consistent with previously published post-mortem data in RLS. With Bonferroni correction, the decrease in thalamic Beta endorphin remained significant (p= .006 x 7= .042). These results suggest that there may be altered central processing of pain in RLS and these data further implicate the endogenous opioid system in the pathogenesis of RLS. The mu opiate receptor subtype may be involved in the pathogenesis of RLS as it is the target of Beta-endorphin and Met-enkephalin but not Leu-enkephalin. However, these results should be viewed as only preliminary and more advanced techniques such as stereology should be employed in future post-mortem studies. In addition, other opioid rich areas need to be explored as well as areas implicated in the pathogenesis of RLS such as the red nucleus and raphe nucleus.
阿片类药物是治疗不宁腿综合征（RLS）体征和症状的有效方法，当给接受阿片类药物治疗的RLS患者以盲法给予阿片受体阻滞剂纳洛酮时，RLS的体征和症状会再次出现。这些数据表明，阿片类药物的作用在RLS中对阿片受体具有特异性，并提示内源性阿片系统及其脑啡肽和内啡肽参与了RLS的发病机制。因此，我们测量了RLS患者（5名女性，平均年龄80.2岁）与对照组（5名女性，1名男性，平均年龄76.3岁）丘脑和黑质中β-内啡肽、甲硫氨酸脑啡肽和亮氨酸脑啡肽的水平。每个大脑的一半固定在磷酸盐缓冲盐水（PBS）中的多聚甲醛（PFA）中用于病理评估，石蜡切片用抗体染色。细胞数量以盲法计数。在丘脑中，与对照组相比，RLS患者中β-内啡肽和甲硫氨酸脑啡肽阳性细胞分别减少了37.5%（p = 0.006，效应大小2.16）和26.4%（p = 0.028，效应大小1.58）。丘脑中亮氨酸脑啡肽以及黑质中β-内啡肽、甲硫氨酸脑啡肽、亮氨酸脑啡肽或酪氨酸羟化酶（多巴胺合成的限速步骤）均无差异。尽管发病机制的主要假说是RLS中存在多巴胺能功能减退，但黑质中酪氨酸羟化酶缺乏减少与之前发表的RLS尸检数据一致。经Bonferroni校正后，丘脑β-内啡肽的减少仍然显著（p = 0.006×7 = 0.042）。这些结果表明，RLS中可能存在疼痛中枢处理的改变，这些数据进一步提示内源性阿片系统参与了RLS的发病机制。μ阿片受体亚型可能参与了RLS的发病机制，因为它是β-内啡肽和甲硫氨酸脑啡肽而非亮氨酸脑啡肽的靶点。然而，这些结果应仅视为初步结果，未来的尸检研究应采用更先进的技术，如体视学。此外，还需要探索其他富含阿片类物质的区域以及RLS发病机制中涉及的区域，如红核和中缝核。
