Researchers discover pain relief pathway with fewer opioids

Better relief for acute pain using fewer opioids may be on the horizon thanks to new research into a chemical compound that targets multiple pain receptors. Researchers found that the addition of one type of protein provided better pain relief at a lower morphine dose in rodents.

Researchers from John Hopkins University School of Medicine added the protein BAM22 to morphine, which ultimately strengthened the opioid's analgesic effect while also limiting some of its adverse effects in rodents (Science Signaling, June 19, 2018). While BAM22 is currently not approved for research in humans, the discovery shows promise for developing similar agents that target multiple pain receptors.

"Activating two different receptors present in the same sensory neurons seems to have a type of synergy that requires less drug to deliver better pain relief in our animal models, and, if tests in humans pan out, may offer a way to lower the risk for developing tolerance and addiction to pain medications," stated study author Srinivasa Raja, MD, a professor of neurology and anesthesiology and critical care medicine, in a press release.

The key to targeting multiple pain receptors

Opioids have proved to reduce severe, acute pain, but they are also associated with a number of adverse effects, including drowsiness, nausea, and headaches. Furthermore, opioid drugs are highly addictive, and patients who regularly use opioids may develop a tolerance to their analgesic effects. Therefore, the researchers wondered if they could achieve adequate pain relief with fewer opioids by targeting multiple pain receptors.

They found promise in BAM22, a protein that activates both opioid receptors and MrgC11 receptors, a group of primary sensory neurons associated with itch and pain sensations. In rodents, MrgC11 receptors bond with opioid receptors. However, unlike the opioid receptors, MrgC11 does not target the central nervous system.

Once the researchers discovered that BAM22 activated these two synergistic pain receptors, they decided to test whether adding BAMM22 to morphine could enhance the opioid's analgesic effect in rodents.

Researchers injected rodents with one of three solutions:

1. Saline
2. Morphine at a typical dose
3. BAM22 with a dose of morphine so low that it is typically considered ineffective

Rodents injected with BAM 22 and morphine showed significantly delayed pain response compared with rodents injected with morphine alone. Furthermore, the rodents injected with the combination showed similar movement patterns and activity to rodents that received saline alone, suggesting that there may be fewer adverse effects.

"One of the limitations of opioid medications is tolerance to the drug," stated senior study author Yun Guan, MD, PhD, an associate professor of anesthesiology and critical care medicine. "To get the same level of pain relief, physicians have to keep escalating the dose. So if we can start with a lower dose of the drug, we may be able to delay tolerance to it and reduce side effects."

Still a long way to clinical use

The study demonstrated the promise of simultaneously activating both MrgC11 and opioid receptors, but scientists are still a long way from a clinical version of the combination. Notably, BAM22 and morphine were injected into rodents' spines, while most opioid analgesics are prescribed through tablets. Furthermore, BAM22 is not approved for human use or experimentation, so researchers would need to develop or discover another compound that activates both types of pain receptors.

Nevertheless, the discovery of the synergistic effect of MrgC11 and opioid receptors is a step toward finding ways to improve the analgesic effect of opioids without as high of a dose. Future studies using mice with MrgX1, the human version of MrgC11, are needed to continue testing the interaction, the researchers noted.

"Our findings suggest the importance of developing drugs that activate both Mrg and [opioid receptors] to boost opioid analgesia and limit central side effects," Dr. Guan stated.