Previous theories about dopaminergic effect on RLS pathophysiology mainly focused on substantia nigra and dopaminergic A11 cell group (Ondo et al., 2000; Trenkwalder and Paulus, 2010), nevertheless, changes in dopaminergic neurons in basal ganglia in RLS patients were also found in autopsy studies. This result might be related to iron deficiency in brain (Connor et al., 2003). Dopaminergic projections to the spinal cord originate exclusively from A11 cell group (Noga et al., 2004). Dopamine acted as an excitatory and inhibitory neurotransmitter in spinal cord to regulate sensory, motor as well as autonomic functions (Dauvilliers and Winkelmann, 2013). Recent studies reported frequent PLMS in patients with spinal cord injury, indicating the center role of spinal cord in RLS pathophysiology process (Dauvilliers and Winkelmann, 2013). It might also result from the decreasing supraspinal inhibition to the spinal cord. Functional MRI studies showed changes of thalamic and cerebral activation in RLS (Bucher et al., 1997). However, postmortem studies in RLS patients showed no evidence of changes in the volume of tyrosine kinase (+) neurons or gliosis changes in A11 region in the posterior hypothalamus (Earley et al., 2009). This might result from the fact that only six cases are included in this study or the hypothesis that the manifestations of RLS may be secondary to dopamine metabolism or changes in the distal A11 synapses which is not as easily detected as structural or quantity changes in the cell bodies (Earley et al., 2009). Another recent study indicated that domperidone, a dopamine antagonist that cannot cross the BBB increased the frequency of RLS in patients with Parkinson’s Disease, proposing that peripheral dopaminergic neurons might play an important role in RLS (Rios Romenets et al., 2013). It’s widely believed that iron deficiency in brain causes the decrease in dopaminergic function which then motivates spinal hyperexcitability, leading to the spontaneous sensory and motor movements of RLS (Garcia-Borreguero and Williams, 2014).