Pathophysiology of restless legs syndrome: Evidence for iron involvement

Abstract

Neuroimaging, analysis of cerebrospinal fluid, and studies on postmortem tissue are generating data that support the concept that iron availability to the brain is a contributory process to, if not a cause of, restless legs syndrome. These data are reviewed and related to the dopaminergic system because of the use of dopamine agents in treating restless legs syndrome.

Does the endogenous opiate system play a role in the Restless Legs Syndrome?: A pilot post-mortem study

“…Additional receptor blocking studies indicate that opioids have their impact on RLS symptoms by modulating the dopamine system: Dopaminergic agonists are also therapeutic in RLS patients but naloxone only reverses the therapeutic effect of opioids whereas dopamine receptor blocking agents reverse the therapeutic effect of either the opioids or dopaminergic agonists [9]. There is possibly a mild functional dopamine deficiency, and a more profound iron deficiency in RLS patients at the nigro-striatal level [10,11]. In an in-vitro animal model of RLS, iron deprivation results in the death of dopaminergic cells in the substantia nigra and this cell death is prevented by the preadministration of opioids to the cells [12].…”

“…In an in-vitro animal model of RLS, iron deprivation results in the death of dopaminergic cells in the substantia nigra and this cell death is prevented by the preadministration of opioids to the cells [12]. In this animal model, dopamine cell death is presumed to be a surrogate for dopamine cell hypofunction given the fact that human autopsy data on RLS patients does not show evidence of a dopamine deficiency [11]. All of these data suggest altered central processing of sensory information in RLS patients and implicate the endogenous opioid system in the sensory and motor aspects of RLS.…”

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

“…In addition, an appraisal of the mechanistic understanding of dopaminergic intervention forms the foundation of the proposed functioning of adenosine analogs, opioids, and ␣ 2 ␦ ligands that are potential treatments for this disease (none are currently approved for the treatment of RLS). While numerous recent articles have highlighted the links between genetics and RLS and the role of brain iron deficiency in RLS [12,13] , these areas are beyond the focus of this review. Here, we examine the actions of other drug classes, including ␣ 2 ␦ ligands, opioids, and adenosine-receptor ligands, and how these might be related to the effects of dopamine agonists in RLS.…”

“…While alternate models may conceivably exist that account for the dopamine hypothesis in RLS (and the beneficial actions of dopaminergics as therapeutics), to our knowledge, none have been proposed that clearly link circuit dysfunction to the RLS phenotype. Although changes in central nervous system (CNS) dopaminergic function have been identified in other regions in association with RLS, including iron metabolism [10,12,15,16] , their correlation may be a secondary consequence of RLS rather than a primary causal factor.…”

“…To date, 2 predominant mechanisms underlying RLS have been proposed in some detail, namely (i) dopaminergic dysfunction [7][8][9] and (ii) brain iron deficiency [10][11][12] . As such, pharmacological intervention to date has been focused on these 2 physiological processes.…”