Restless Legs Syndrome and the Melanocortin System
Abstract
The objective of this proposal is to study the underlying biological mechanisms of restless legs syndrome (RLS), which will guide future research to identify novel and specifically targeted drug treatments for RLS. RLS is a chronic, progressive neurologic disease that affects between 5% and 10% of U.S. adults and 14% of U.S. Veterans. RLS consists of an unrelenting urge to move at night, which prevents sleep and limits sitting to minutes at a time during the day. Veterans who develop RLS are at increased risk of accelerated mortality, heart disease, and stroke. Also, those with RLS are more likely to have had suicidal ideation or a suicide attempt over their lifetime. Despite the obvious clinical relevance of RLS and the fact that RLS often requires lifelong medical therapy, medication options for RLS are limited. This is despite an urgent need for new medicines, as the most commonly used medicines to treat RLS, dopamine medications, actually cause a paradoxical worsening of RLS and a need to switch to alternative therapy in a phenomenon called augmentation. The use of dopamine medication to treat RLS reflects poor disease understanding, as it is now known that RLS is associated with excess brain dopamine, not a deficit as was previously thought. Thus, the biologic paradigm explaining RLS is incomplete and its clarification is critical if increasingly precise RLS medicines are to be developed. The Topic Area guiding this work is the precision treatment of sleep disorders, namely RLS. In order to identify targeted treatments for RLS, it is critical to understand the underlying biological mechanisms of RLS. We propose to study the hormonal melanocortin (MC) system in humans with RLS, based upon multiple similarities between the MC hormones and features of RLS. Central to RLS are an urge to move associated with sensory discomfort and increased movement to alleviate symptoms. The MC hormones are well known to mediate increased locomotion and increased pain sensitivity in rats and cause motor restlessness in humans when given intravenously. MC hormones also promote sleeplessness and involuntary sleep-related limb movements in rats. Thus, the MC hormones given to rats recapitulate the hallmark motor and sensory symptoms of RLS along with salient sleep-related changes. These observations led us to formulate our central hypothesis that increased MC hormone levels cause the symptoms of RLS, which we will study for the first time in humans. In this proposal, we will evaluate MC biology in humans by measuring MC hormone levels in blood and cerebrospinal fluid (fluid surrounding the brain) of persons with RLS compared to persons without RLS. We hypothesize that MC hormone levels will be higher in persons with RLS. Also, we will assess severity of RLS symptoms, sleep disruption, pain sensitivity, depression, and suicidality. We hypothesize that MC hormone levels will correlate to the severity of RLS and degree of change in RLS-related physiologic measures. The study of MC hormones in RLS has potential to be paradigm-shifting, as most research aiming to clarify the biologic mechanisms of RLS has focused on dopamine and iron systems. This award will allow us to demonstrate MC hormone changes in patients with RLS. When paired with the rationale as to why these MC changes result in the symptoms and related physiology of RLS (as outlined above), this research will cause many in the field to refocus their thinking and research of what biologic mechanisms underlie RLS. Much research in RLS biology has focused on iron and dopamine systems. It is worth noting that the MC hormone may unify this prior research as the MC system has intimate links to both iron and dopamine systems. The production of MC hormones in the brain is directly decreased by dopamine, which would explain why giving a dopamine medicine would decrease symptoms of RLS. MC hormones also stimulate the production of a critical stress hormone, called cort
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010003
Entities
People
- Brian Koo
Organizations
- United States Army
- Yale University