Thanks to the scientists from the Department of Infection and Immunity of the Luxembourg Institute of Health (LIH), they have developed a novel molecule called LIH383. The molecule 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.
Scientists developed this molecule based on a past study that 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.
Opioid peptides are small proteins that act as neuromodulators by interacting with four ‘classical’ opioid receptors on the surface of CNS cells, playing a pivotal role in mediating pain relief but also emotions such as euphoria, anxiety, stress, and depression.
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 new study, scientists have come up with 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. The molecule 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.
Scientists demonstrated that ACKR3 has a high affinity for a variety of opioids, to be specific those having a place with the enkephalin, nociceptin, and dynorphin families. In any case, the cooperation among ACKR3 and these opioids don’t generate the typical pain- relief or tranquilizing ‘messages’ that emerge when opioids tie to the alleged ‘old style’ opioid receptors.
Max Meyrath, a co-first author of the study, said, “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.”
Dr. Martyna Szpakowska, co-first author of the publication, said, “Our findings essentially brought forward a new and previously unknown mechanism to fine-tune the opioid system and modulate the abundance of natural opioids by manipulating the fifth member of the opioid receptor family, ACKR3. We, therefore, set about developing a molecule that would be able to tightly bind to and block ACKR3, to potentiate the beneficial natural effects of opioids on pain and negative emotions. This is how LIH383 was conceived.”
The study has opened up new treatment of chronic pain, stress, anxiety, and depression, but also for cancer therapy. Indeed, aside from its newly-described role as an opioid receptor, ACKR3 was originally known as a chemokine receptor for its ability to also bind to chemokines — small proteins secreted by immune cells which mediate immune responses but which have also been shown to be involved in tumor initiation and metastasis.
Indeed, aside from its newly-described role as an opioid receptor, ACKR3 was originally known as a chemokine receptor for its ability to also bind to chemokines — small proteins secreted by immune cells which mediate immune responses but which have also been shown to be involved in tumor initiation and metastasis.
Dr. Chevigné said, “As an ACKR3 modulator that interacts and ‘interferes’ with ACKR3, LIH383 therefore also holds promise for the treatment of metastatic cancers, leveraging on our remarkable discovery of the dual chemokine-opioid ‘scavenging’ activity of this receptor. We expect LIH383 to act as a precursor for the development of a new class of drugs against pain and depression, thus offering an innovative and original therapeutic strategy to tackle the opioid crisis.”
Prof Markus Ollert, Director of the LIH Department of Infection and Immunity and co-author of the study, said, “This is a glaring example of the way fundamental research can be translated into concrete applications with tangible benefits for patients, leading to improved clinical outcomes. The success of our work was only made possible by the generous and unwavering support of the Luxembourg National Research Fund, the Ministry of Higher Education and Research, as well as the charitable initiative ‘Télévie.'”
- Saori Araki et al. miR2118-dependent U-rich phasiRNA production in rice anther wall development. Nature Communications. DOI: 10.1038/s41467-020-16637-3