New Molecule Offers Renewed Hope for Treatment of Pain, Anxiety, Stress, and Depression

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

Novel molecule targets a newly discovered opioid receptor with atypical properties and holds promise for alternative therapeutic strategies.

Researchers at the Department of Infection and Immunity of the Luxembourg Institute of Health (LIH) developed LIH383, a novel molecule that binds to and blocks a previously unknown opioid receptor in the brain, thereby modulating the levels of opioid peptides produced in the central nervous system (CNS) and potentiating their natural painkilling and antidepressant properties. Opioid peptides are small proteins that act as neuromodulators by interacting with four ‘classical’ opioid receptors on the surface of CNS cells, playing a key role in mediating pain relief but also emotions such as euphoria, anxiety, stress, and depression. The molecule was developed by Dr. Andy Chevigné, Head of Immuno-Pharmacology and Interactomics at LIH, and his team, based on their previous research that had identified the atypical chemokine receptor ACKR3 as a novel opioid receptor which binds to natural opioids and ‘traps’ them, thereby dampening their analgesic and antianxiety activity. These findings were published on June 19th in the prestigious international journal Nature Communications, carrying important implications for the development of a novel class of drugs for pain, depression, and for brain cancer treatment.

Opioid-related disorders such as severe pain are currently predominantly treated through drugs that act on the opioid system. Opioid prescription drugs against pain — including morphine, oxycodone, and fentanyl — work by targeting and activating opioid receptors, preventing the natural ‘pain message’ from being transmitted, altering pain perception and consequently resulting in painkilling effects. Despite their effectiveness, the use of these painkillers frequently leads to several side-effects, such as tolerance, dependence and respiratory disorders. Therefore, there is an urgent need to find new means to modulate the opioid system by using drugs with novel mechanisms of action and reduced complications, particularly given the current public health crisis, known as the “opioid crisis,” linked to the growing abuse of and addiction to synthetic opioids.

In this context, the LIH research team led by Dr Chevigné developed and patented a novel molecule — LIH383 — that has the overall effect of increasing the availability of opioid peptides that bind to classical opioid receptors in the brain.

Specifically, LIH383 works by targeting and blocking the atypical chemokine receptor ACKR3, which the LIH researchers had shown to be a new opioid receptor with negative regulatory properties. The scientists demonstrated that ACKR3 possesses a high affinity for a variety of opioids, namely those belonging to the enkephalin, nociceptin, and dynorphin families. However, the interaction between ACKR3 and these opioids does not generate the typical pain-relief or tranquilizing ‘messages’ that arise when opioids bind to the so-called ‘classical’ opioid receptors.

“Interestingly, we found that ACKR3 does not trigger the distinctive chain of molecular signaling events that results in painkilling effects. Instead, ACKR3 functions as a ‘scavenger’ that sequestrates the opioids that would otherwise bind to the classical receptors. In other words, ACKR3 is an atypical opioid receptor that traps the secreted opioid peptides and reduces the levels that can interact with traditional receptors, therefore mitigating their action and acting as a negative regulator of the opioid system,” explains Max Meyrath, co-first author of the study.

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