Researchers at the Department of Infection and Immunity of the Luxembourg Institute of Health (LIH) have developed a novel molecule that binds to and blocks a previously unrecognized opioid receptor in the brain. The team’s studies showed that using the molecule, LIH383, to block this atypical opioid receptor, which is known as ACKR3, increases the availability of opioid peptides produced in the central nervous system (CNS) to bind to classical opioid receptors, effectively increasing their natural painkilling and antidepressant properties. The research could point to the development of a novel class of drugs for treating pain, depression, and also brain cancer.
“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,” said Martyna Szpakowska, PhD, co-first author of the team’s publication in Nature Communications, which is titled, “The atypical chemokine receptor ACKR3/CXCR7 is a broad-spectrum scavenger for opioid peptides.”
Opioid receptors are G protein-coupled receptors (GPCRs) that play a central role in reward processing, euphoria, analgesia, stress, anxiety, and depression, the authors explained. There are three classical receptors, designated mu, delta, and kappa, and a fourth, non-classical nociception receptor, NOP. Opioid peptides are small proteins that act as neuromodulators by interacting with these opioid receptors on the surface of CNS cells, playing a key role in mediating pain relief, and also modulating emotions.
Severe pain is predominantly treated using drugs that act on this opioid system. Prescription opioid drugs—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. However, while such drugs are effective, their use frequently leads to several side effects, such as tolerance, dependence, and respiratory disorders.
These drawbacks mean that there is an urgent need to find new strategies for modulating the opioid system by using drugs with novel mechanisms of action and reduced complications, particularly given the current public health crisis, which is linked to the growing abuse of and addiction to synthetic opioids, the team continued. “… a better understanding of opioid receptor signaling regulation and bias as well as new strategies to modulate opioid receptors with less adverse effects are not only timely but also urgently needed, especially considering the current opioid crisis.”
Andy Chevigné, PhD, head of immuno-pharmacology and interactomics at LIH, and his team, have developed LIH383 based on their previous research that had identified the atypical chemokine receptor, ACKR3, as a novel opioid receptor that has negative regulatory properties. The scientists demonstrated that ACKR3 possesses a high affinity for a variety of opioid peptides. However, the interaction between ACKR3 and these opioids doesn’t generate the typical pain-relief or tranquilizing signals that arise when opioids bind to the classical opioid receptors. Rather, ACKR3 was found to trap natural opioids and so dampen their analgesic and anxiolytic activities. “Functionally, ACKR3 is a scavenger receptor for a wide variety of opioid peptides, especially enkephalins and dynorphins, reducing their availability for the classical opioid receptors,” the authors wrote.
“Interestingly, we found that ACKR3 does not trigger the distinctive chain of molecular signaling events that results in painkilling effects,” said Max Meyrath, PhD, co-first author of the study. “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.”
The team also found that none of the small drugs—such as morphine, fentanyl, or naloxone—that target the classical opioid receptors worked to activate or inhibit ACKR3. “We, therefore, set about developing a molecule that would be able to tightly bind to and block ACKR3, with the aim of potentiating the natural beneficial effects of opioids on pain and negative emotions,” Szpakowska said. “This is how LIH383 was conceived.”
LIH383 effectively targets and blocks ACKR3, and so has the overall effect of increasing the availability of opioid peptides that bind to classical opioid receptors in the brain. “ACKR3 is an atypical opioid receptor and does not induce classical G protein signaling upon opioid peptide binding but rather internalizes these peptides in order to regulate their availability for classical opioid receptors,” the investigators reported. “Interestingly, blocking ACKR3 with LIH383 positively impacted on the availability and signaling of opioid peptides through classical receptors in a rat ex vivo model, providing an original and indirect alternative to modulate the system.”
The reported results offer up new insights into opioid system function that could lead to the development of alternative therapeutic strategies. “In conclusion, the identification of ACKR3 as negative regulator of opioid peptide function adds another level of complexity and fine-tuning to the opioid system but also opens additional therapeutic opportunities,” the authors concluded.
The team’s results could help in the design of alternative options for the treatment of chronic pain, stress, anxiety, and depression, and also for cancer therapy. Aside from its newly described role as an opioid receptor, ACKR3, which was originally known as CXCR7, was previously identified as an atypical chemokine receptor also binds to chemokines— small proteins secreted by immune cells, which mediate immune responses, and which have also been shown to be involved in tumor initiation and metastasis. Specifically, ACKR3 is expressed abundantly in tumors such as glioblastoma and breast cancer, and its presence correlates with increased tumor growth, metastasis, resistance to chemotherapy, and poor prognosis.
“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,” stated Chevigné. “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.”
“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,” commented Markus Ollert, PhD, director of the LIH Department of Infection and Immunity and co-author of the study. A patent application covering the team’s developments was filed in April 2020.