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New research suggests that a compound that exists naturally in the pinwheel flower may help treat chronic pain. Bosir Ahmed/Getty Images
  • The body’s opioid system regulates its response to pain, and many opioid medications target this system for chronic pain relief.
  • However, opioid drugs can have dangerous long-term side effects. Additionally, scavenger receptors can negatively regulate the effectiveness of naturally produced opioids in the body.
  • A new study shows that the compound conolidine, found in the pinwheel flower, only binds to one particular scavenger receptor. Researchers believe that blocking this scavenger receptor means that it can no longer prevent naturally produced opioids from interacting with other opioid receptors that promote pain relief.

The opioid system in the human body comprises many proteins, receptors, and other compounds that all play a vital role in controlling people’s pain responses and behaviors toward reward and addiction.

In addition to the body’s naturally produced proteins, known as opioid peptides, there are opioid analgesic medications. These include drugs such as morphine and oxycodone, which doctors often prescribe to treat chronic pain.

These drugs, which mimic the function of the opioid peptides, can have significant side effects when people take them frequently or in high amounts. Not only can they cause respiratory depression, constipation, and nausea, but they are also highly addictive in nature and have led to increasing rates of fatal overdose.

The opioid crisis is a public health crisis that is further tied to racial and economic disparities, and finding alternative therapeutic options to address chronic pain is just one part of the solution.

A recent study, which features in the journal Signal Transduction and Targeted Therapy, showed that a plant-derived compound called conolidine might work to increase opioid peptides’ pain-regulating activity, suggesting that it could be a safer alternative to opioid drugs.

Scientists at both the Immuno-Pharmacology and Interactomics group of the Luxembourg Institute of Health (LIH) and the Center for Drug Discovery at RTI International in North Carolina conducted this collaborative study.

In the body, opioid peptides interact with and bind to classical opioid receptors. There are four types of classical opioid receptors, which are mostly in the central and peripheral nervous systems. The interactions between the opioid peptides and classical receptors trigger a cascade of protein signaling functions that eventually lead to pain relief.

However, when the same researchers at LIH conducted a previous study, they identified an atypical opioid receptor called ACKR3. This receptor also binds to opioid peptides, but instead of leading to pain relief, it traps the peptides and prevents them from binding to any of the classic receptors, thus potentially preventing pain modulation.

Furthermore, the researchers discovered the ACKR3 receptor at high levels in key brain regions that are also important opioid activity centers.

The research team described the receptor as an “opioid scavenger” because of its ability to trap naturally occurring opioids before they can interact with classical opioid receptors.

In response to this issue, the new study looked into conolidine, a molecule that is present in the bark of the pinwheel flower and commonly used in traditional Chinese, Ayurvedic, and Thai medicine due to its analgesic properties.

In a screening test involving more than 240 receptors, the researchers found that conolidine demonstrated binding to the ACKR3 receptor in both humans and mice, preventing ACKR3 from binding to opioid peptides.

Additionally, the conolidine molecule did not interact with the classical receptors, meaning that it would not compete against opioid peptides to bind to these receptors.

These results suggest that conolidine is able to restrict the ACKR3 receptor’s negative regulatory properties and free up opioid peptides, allowing them to bind to the classical opioid receptors and promote analgesic activity.

The scientists also extended their findings by chemically modifying conolidine to create a new compound, RTI-5152-12, which binds specifically to the ACKR3 receptor. In comparison with the natural conolidine, this synthetic compound showed increased binding to the ACKR3 receptor, making it a more effective potential treatment option.

According to the LIH press release, the two research teams filed a joint patent application for RTI-5152-12 in December 2020. The study authors state:

“Overall, the discovery of the potential mode of action of conolidine and its activity on ACKR3 is a significant step forward toward a more exhaustive understanding of its role in pain regulation, bearing great potential for novel drug development against chronic pain.”

Although this study identifies the correlation between conolidine and ACKR3, the mechanism of action following the binding interaction is not yet clear. Nevertheless, conolidine may have minimal side effects in comparison with opioid drugs, and it opens an exciting avenue into the research of the opioid system.