Possible Sites of Therapeutic Action in Restless Legs Syndrome: Focus on Dopamine and α2δ Ligands

Restless legs syndrome (RLS) is a common sensorimotor disorder characterized by abnormal sensations that occur primarily at rest or during sleep, which are alleviated by movement of the affected limb. The pathophysiology of RLS remains unclear, although roles for dopamine dysfunction and brain iron deficiency have been proposed. The hypothalamic A11 dopaminergic circuit is used to explain the dopamine dysfunction in RLS and the potential therapeutic actions of dopamine D(2) agonists. Modulation of central and peripheral neuronal circuits may also explain the potential therapeutic sites of action of opioids, adenosine receptor ligands, and voltage-gated calcium channel α(2)δ ligands in RLS. The known and possible therapeutic benefits of these agents and their relationship to dopaminergic dysfunction in RLS are discussed in this review.