Novel molecule: New hope for the treatment of pain and depression

 

Researchers at the Luxembourg Institute of Health (LIH) are developing a novel molecule that binds to and blocks a previously unknown opioid receptor in the brain – holding great promise for the design of alternative therapeutic strategies.

The LIH team has developed a molecule that improves the pain and antidepressant properties of molecules naturally produced in the brain, known as “opioid peptides”. Opioid peptides are small proteins that are produced naturally, e.g. in the brain.

They influence a variety of feelings and biological processes, such as motivation, euphoria, affection and responses to stress and pain. They perform their natural analgesic and antidepressant functions by interacting with four specific opioid receptors (so-called “molecular switches”) located on the surface of brain cells. They play a key role in mediating pain and emotions such as euphoria, anxiety, stress and depression.

The revolutionary molecule developed by Luxembourg researchers – called LIH383 – binds to and blocks a fifth receptor in the brain. This receptor is unusual and so far little studied. The LIH383 molecule has important implications for the development of a new class of drugs for acute and chronic pain, for depression but also for the treatment of brain cancer.

How do opioid painkillers such as morphine & co. work?

The opioid system is complex and its functioning is not yet fully understood. In response to stress, the body releases its own opioids, for example to suppress acute pain or hunger. Other opioids produced by the body, such as endorphin, can cause euphoria. Natural opioids are released by the body in the event of injury, emotional stimuli and also as a result of exposure to UV light. Opioids bind to opioid receptors on the surface of nerve cells, mainly in the brain, but also in the spinal cord and in the intestine.

Synthetic opioid drugs commonly used to treat acute pain – including morphine, oxycodone and fentanyl – act by targeting and activating the same receptors. Despite their effectiveness, these analgesics are frequently associated with several side effects, such as addiction and breathing problems. There is therefore a real need to discover new pain medications with different mechanisms of action resulting in a lower risk of complications, particularly in view of the current public health crisis, known as the “opioid crisis”, linked to the abuse of and increasing dependence on synthetic opioids.

A new molecule and an unusual opioid receptor

In this context, the LIH research team, led by Dr. Chevigné, developed LIH383. The LIH383 molecule binds to an unusual opioid receptor called ACKR3, which has so far been little studied in this context.

“We have been able to show that ACKR3 can bind to a wide range of opioids, particularly in the central nervous system (brain, spinal cord) and negatively regulate the opioid system. It does this by ‘capturing’ naturally occurring opioids that would normally bind to and activate the four conventional opioid receptors. “The ACKR3 opioid receptor therefore reduces the availability of naturally occurring opioids in the nervous system, thereby indirectly reducing their analgesic and anxiolytic activity.” – Dr. Andy Chevigné, PI on the study.

A new class of drugs?

The new molecule LIH383 binds to and blocks the ACKR3 receptor. It therefore prevents the receptor from capturing naturally secreted opioids. In total, LIH383 increases the availability and use of opioids naturally secreted by the brain.

“Our results essentially led to a previously unknown mechanism for refining the opioid system and therapeutically affecting the availability of naturally occurring opioids by targeting ACKR3, the fifth member of the opioid receptor family,” Chevigné concludes.

“We expect LIH383 to act as a precursor for the development of a new class of drugs for pain and depression, providing a novel and innovative therapeutic strategy to address the opioid crisis,” said the study’s first two co-authors Max Meyrath and Dr. Martyna Szpakowska.

What are the next steps?

“The molecule is a kind of prototype, which we initially tested only in so-called ‘ex vivo’ models, in particular in tissue sections from rat brains. Of course, we still need to do a lot of in vivo experiments (editor’s note: in a living organism) and improve the molecule,” says Chevigné.

He continues: “We are currently developing the second generation of the LIH383 molecule and have begun discussions on how best to move this program forward, i.e. with which partners (private, public), with which models (in vivo) and with which funding.”

There is now a need to study how manipulation of the ACKR3 receptor affects pain, stress and addiction, which are possible side effects on both the opioid and chemokine systems,” said Chevigné. Because the ACKR3 receptor also captures chemokines – messenger substances that play a role in many areas, particularly the immune system.

In addition to alternative options for treating chronic pain, stress, anxiety and depression, these findings could also open the door to new cancer treatments. Indeed, scientists believe that this molecule could also help slow down tumour growth and the development of metastases in brain cancer, leading to a better prognosis for patients.

“We have been investigating ACKR3 in the context of glioblastoma multiforme (editor’s note: the most aggressive brain tumour) for more than six years. We know that there is more ACKR3 in glioblastoma and also in the blood vessels associated with the tumour. And that there is a positive effect when we target the receptor therapeutically. But we haven’t tested LIH383 in glioblastoma multiforme yet, but we’d like to try it in the near future.” – Andy Chevigné.

From basic research to real-world applications

“We originally developed LIH383 to prove that the ACKR3 is a so-called ‘scavenger receptor’, which means it can capture opoids,” says Chevigné. “As soon as we were finished, we quickly recognized its potential as a prototype for a new class of therapeutic molecules,” said Chevigné.

“This discovery is a prime example of how basic research can be translated into concrete applications with tangible benefits for patients, leading to better clinical outcomes,” said Professor Markus Ollert, Director of the Department of Infection and Immunity at the LIH and one of the co-authors of the publication. “The success of our study was made possible thanks to the generous and unfailing support of the FNR, the Ministry of Higher Education and Research, and the charity initiative Télévie,” he concludes.

Scientific publication

Dr Andy Chevigné, head of the Immuno-Pharmacology and Interactomics research group at the Department of Infection and Immunity of the Luxembourg Institute of Health (LIH), in collaboration with his team, published [open access] the results of the study –  ‘The atypical chemokine receptor ACKR3/CXCR7 is a broad-spectrum scavenger for opioid peptides’ on 19 June in the international journal “Nature Communications”.

Read more about this research on the LIH website

Funding and research teams

This study was supported various FNR programmes including PRIDE and PEARL. It was also supported by the Ministry of Higher Education and Research (MESR); the Fonds de la Recherche Scientifique – FNRS-Télévie; Pelican Foundation; German Research Foundation (Deutsche Forschungsgemeinschaft – DFG).

The study was performed in close collaboration with national and international partners, and involved LIH’s Department of Infection and Immunity, LIH’s Transversal Translational Medicine unit, the Luxembourg Centre for Systems Biomedicine (LCSB) at the University of Luxembourg, the Department of Life Sciences and Medicine of the University of Luxembourg, the Molecular, Cellular and Pharmacobiology Section of the Institute of Pharmaceutical Biology of the University of Bonn (Germany), the Neurophysiology Unit of the University of Liège (Belgium), the Research Training Group of the University of Bonn (Germany) and the Department of Dermatology and Allergy of the Odense Research Center for Anaphylaxis (ORCA) at the University of Southern Denmark (Denmark).

From left to right: Dr Andy Chevigné, Dr Martyna Szpakowska and Max Meyrath

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