A large number of pharmacological studies and clinical findings have provided evidence for the important role of dopaminergic system dysfunction in RLS (Winkelmann et al., 2001; Paulus and Trenkwalder, 2006; Galbiati et al., 2015). An improvement of RLS symptoms was found in patients receiving low-dose dopaminergic medications (Paulus and Trenkwalder, 2006; Galbiati et al., 2015) while a worsening of RLS symptoms in patients receiving dopamine antagonists (Winkelmann et al., 2001). The need for dopaminergic agonists to cross the BBB to be effective in RLS symptoms indicated that dopaminergic system in central nervous system was entailed in RLS pathophysiology rather than in peripheral nervous system (Garcia-Borreguero and Williams, 2014). Tyrosine hydroxylase is a rate-limiting step enzyme for the conversion of levodopa to dopamine. As iron is a cofactor of this enzyme, iron deficiency can alter the dopaminergic system in the brain (Dauvilliers and Winkelmann, 2013). Dopaminergic A11 cells, located in the midbrain and close to hypothalamus, have long axons and project diffusely throughout the spinal cord (Clemens and Hochman, 2004). They are the major source of dopamine in spinal cord. A11 cells arrive in the dorsal horn, then project to the motoneuronal site (Holstege et al., 1996). It’s found that stereotaxic bilateral 6-hydroxydopamine lesions into the A11 nucleus can result in an increased average number of standing episodes and total standing time comparing to the sham rats (Ondo et al., 2000), suggesting an important role of A11 dopaminergic cells in pathophysiological pathways in RLS. A significantly decreased N-acetylaspartate, creatinine ratio, and N-acetylaspartate concentrations were found in the medial thalamus of RLS patients in a recent study using proton magnetic resonance spectroscopy (Rizzo et al., 2012). Functional MRI and PET studies concluded an important role of medial thalamic nuclei in RLS pathophysiology. The medial thalamic nuclei are part of the limbic system, which is modulated by dopaminergic afferents. Another study found thalamic activity changes in the thalamocotrical circuit (Goulart et al., 2014). Therefore, it was hypothesized that the dopaminergic dysfunction might lead to an impairment of the medial pain system (Garcia-Borreguero and Williams, 2014; Goulart et al., 2014) and then caused the uncomfortable symptoms of RLS. Pharmacological studies also demonstrated that opioids had a protective effect in some RLS patients. An in vitro study in rats found that iron deficiency can cause cell death, mainly dopaminergic cells in substantia nigra and opioids could protect them from cell death under the condition of iron deprivation (Sun et al., 2011). The authors concluded from this result that an intact endogenous opioid system and opioid treatment could prevent the dopamine system from dysfunction in iron deficiency patients (Sun et al., 2011). A study of tsDCS in RLS patients showed supportive evidence of spinal cord hyperexcitability (Heide et al., 2014).