With a more accurate understanding of the characteristics and function of the receptor MRGRPX2, University of North Carolina School of Medicine researchers were also able to create chemical probe that will allow them study the receptor more precisely.
New findings published in the journal Nature Chemical Biology by UNC School of Medicine scientists show that MRGRPX2, a receptor protein on the surface of mast cells, can trigger the immune system response that leads to itching associated with some opioids.

Kate Lansu, the paper’s first co–author and a graduate student in the lab of Bryan Roth, MD, PhD, explains how this process works.

“Receptors in mast cells – part of the immune system – respond to an activation signal and release inflammatory factors like histamine, in a process called degranulation,” she said. “When that happens, other cells are recruited to the site of inflammation to clear the infection. This response is also important for things like allergies. And this is what presents itself as itching.”

“Opioid drugs have been link to degranulation also, but it was through an unknown mechanism. We think that our data could potentially explain why degranulation occurs as a side effect of opioid ligands (morphine and other drugs), something that is well–known but not well–understood.”

The findings are significant not only because they offer a potential explanation for opioid–induced itching, but also because the data suggest a way to characterize the function of the orphan receptor MRGRPX2.

Currently there are about 120 orphan receptors in humans. They are “orphan” because, though we know they exist, we don’t yet know what they do. The Roth lab screens these receptors against thousands of small molecules to find out what might activate them. This process involves a combination of physical screening and computational modeling.

“Working on MRGRPX2, I screened around 7,000 molecules, and that data gave us a sense of what the binding site might look like. Once that tentative picture was in place, we were able to use computational tools to create a more precise model of the site,” Lansu said.

The computer modeling, performed by co–first author Joel Karpiak, a graduate student at the University California at San Francisco, tested 3.7 million models for potential interaction with the receptor.

“And that’s so many more different types of chemicals than I could do by hand in an assay,” said Lansu.

The physical data combined with the computational models allowed the researchers to create a chemical probe designed to interact specifically with MRGRPX2. This new tool made it possible to gain a more precise understanding of this receptor’s effects without the noise of other receptors. An opioid might activate the orphan receptor, but it might also activate other receptors that it interacts with.

Imagine trying to recreate a musical score by listening to an orchestra perform a piece of music. “You hear the whole ensemble play and you might think ‘this is very moving’ but it may not explain much about how that effect is achieved,” Lansu said. “But if you had a tool that allowed you to isolate just the trumpets, for example, it could teach you something about how that part contributes to the whole – something you may not be able to hear otherwise.”

Understanding what triggers the itching response could help pharmacologists develop an antagonist for this receptor to reduce the itching side effect. In other cases, clinicians may want to induce histamine release, thereby boosting the immune response, as in the case of vaccine adjuvants, where an increased immune response may improve immunity. These findings suggest there may be a way to do that selectively.