Restless Legs Syndrome Foundation Blog

August 6, 2019

New Study Funded by RLS Foundation

By Kris Schanilec

The RLS Foundation has awarded a grant of $36,398 to Sergi Ferré, MD, PhD, of the National Institute on Drug Abuse, for a study to explore how opioid medications work in the brain to relieve RLS symptoms. This research builds on several Foundation-funded studies previously conducted by Dr. Ferré, who is a member of the RLS Foundation Scientific and Medical Advisory Board.

“Dopamine agonists, alpha-2 delta agents and opioids are highly effective in treating RLS,” says Christopher J. Earley, MB, ChB, PhD, FRCPI, chair of the Scientific and Medical Advisory Board. “Dr. Ferré’s grant is the first to try and understand the biologic elements that may be common to these three classes of drugs that makes them so effective in treating RLS, thus opening the door for future drug development.”

Opioid medications act on three types of opioid receptors in the brain. One of these – the mu opioid receptor – is the target of the opioid medications, such as methadone, that are a very effective treatment for severe RLS when used in low total daily doses. RLS is a neurological disease that has a distinctly different underlying neuropathology than that associated with typical pain syndromes. Clinical experience among experts who use opioids to treat severe RLS has not shown the degree of drug misuse, dependency or addiction that is commonly associated with opioid use to treat chronic pain.*

In the current study, “Elucidating the mechanisms of the therapeutic effects of opioids in RLS,” Dr. Ferré’s team aims to identify the locations of mu opioid receptors involved in improving RLS symptoms with opioids. With this information, they hope to determine if specific opioid medications could selectively act on these mu opioid receptors, reducing the risk of unwanted side effects.

In previous studies funded by the RLS Foundation, Dr. Ferré’s laboratory developed an animal model for RLS using a brain iron-deficient rodent that models the brain iron deficiency that is characteristic of RLS in humans. Their model combines two techniques, optogenetics and microdialysis, to trigger and measure the release of glutamate from brain cells in live animals. The researchers used this model to confirm that brain iron deficiency increases the release of glutamate in the brain area known as striatum; other studies have reported increased glutamate in the RLS brain.

Dr. Ferré’s team also validated that several RLS drugs – the dopaminergic drugs pramipexole and ropinirole, and the alpha- 2-delta ligand gabapentin – work by counteracting this high release of glutamate. In addition, the researchers pinpointed a subtype of receptor in the brain – the dopamine D4 receptor – as a main target for the effects of the dopaminergic drugs in the striatum, and therefore, as a new target for drug development.

In a more recent study, Dr. Ferré’s laboratory reported that low levels of receptors of the neurochemical adenosine are responsible for the high levels of glutamate released in the striatum. This finding has led to exploration of drugs that increase adenosine levels in the brain – for example, dipyridamole – as a new treatment approach for RLS. According to Dr. Ferré, the reduced levels of adenosine receptors (specifically, the adenosine A1 receptors) may be the underlying cause of not only restless legs, but also the state of enhanced wakefulness (hyperarousal) experienced by people who have RLS.

In the current study, the researchers will focus on a specific neuron in the striatum, the cholinergic interneuron, which releases the neurotransmitter acetylcholine and has a high number of both adenosine A1 receptors and mu opioid receptors. The researchers hypothesize that in RLS, there are fewer adenosine A1 receptors in these cholinergic interneurons, which therefore become overactive and release more acetylcholine. The researchers also hypothesize that opioids should be able to counteract this by activating mu opioid receptors in the cholinergic interneurons. Dr, Ferré’s team will use its animal model to explore these questions.

“If the results of the study confirm our hypotheses, we will have probably found the main mechanism of the therapeutic effect of opioids in RLS,” says Dr. Ferré. “Those results would then stimulate the search for opioids with a preferential efficacy for the mu opioid receptors localized in the striatum, in the cholinergic interneurons, which should be absent of unwanted side effects.”

The RLS Foundation is grateful for the generosity of individuals whose financial gifts make this work possible, says Executive Director Karla Dzienkowski. “The Foundation’s research grant program is dedicated to find better treatments and, ultimately, a cure for RLS. This study will help us to understand why opioid medications are effective at relieving severe, unrelenting symptoms of restless legs syndrome, which will lead to an improved quality of life for people with RLS,” Dzienkowski says.

*If opioid therapy is a treatment option to manage your RLS symptoms, your healthcare provider will work closely with you to find the dose that manages your symptoms while minimizing side effects of therapy.