The Itch Receptor - Kate Lansu leads research on opioid-induced itching

Researchers in the department of Pharmacology link orphan receptor MRGRPX2 to opioid-induced itching and create a tool to study the receptor more precisely.

The Itch Receptor - Kate Lansu leads research on opioid-induced itching click to enlarge Kate Lansu, graduate student in Bryan Roth's lab (photo by Matt Englund)
The Itch Receptor - Kate Lansu leads research on opioid-induced itching click to enlarge PRESTO-Tango Screening of MRGPRX2 reveals new agonists. Learn more about this Venn diagram in the Nature Chem Biol article; link and citation are listed below.

CHAPEL HILL, NC – Opioids have long been an important tool in the world of pain management, but the side effects of these drugs – from addiction and respiratory failure to severe itching and dizziness, can be overwhelming. Scientists have been trying to understand how these side effects happen so they can create better, less problematic pain relievers.

New findings published in the journal Nature Chemical Biology by UNC School of Medicine scientists in the department of pharmacology 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.”

“We start with the physical screening data to give us a sense of what types of molecules interact with the receptor,” Lansu said. “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.”

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. 

~Above article is excerpted from the full article by Matt Englund on SOM Newsroom - read the full article here.

The primate-exclusive MRGPRX2 G protein-coupled receptor (GPCR) has been suggested to modulate pain and itch. Despite putative peptide and small-molecule MRGPRX2 agonists, selective nanomolar-potency probes have not yet been reported. To identify a MRGPRX2 probe, we first screened 5,695 small molecules and found that many opioid compounds activated MRGPRX2, including (-)- and (+)-morphine, hydrocodone, sinomenine, dextromethorphan, and the prodynorphin-derived peptides dynorphin A, dynorphin B, and α- and β-neoendorphin. We used these to select for mutagenesis-validated homology models and docked almost 4 million small molecules. From this docking, we predicted ZINC-3573-a potent MRGPRX2-selective agonist, showing little activity against 315 other GPCRs and 97 representative kinases-along with an essentially inactive enantiomer. ZINC-3573 activates endogenous MRGPRX2 in a human mast cell line, inducing degranulation and calcium release. MRGPRX2 is a unique atypical opioid-like receptor important for modulating mast cell degranulation, which can now be specifically modulated with ZINC-3573.

Lansu K, Karpiak J, Liu J, Huang XP, McCorvy JD, Kroeze WK, Che T, Nagase H, Carroll FI, Jin J, Shoichet BK, Roth BL. In silico design of novel probes for the atypical opioid receptor MRGPRX2. Nat Chem Biol. 2017 Mar 13. doi:
10.1038/nchembio.2334. [Epub ahead of print] PubMed PMID: 28288109.

Other UNC authors on the paper are: Xi-Ping Huang, PhD, and Wesley K. Kroze, PhD, research assistant professors in the UNC department of Pharmacology; UNC research associates John D. McCorvy, PhD, and Tao Che, PhD, also in the UNC department of Pharmacology; and senior author, Bryan Roth, MD, PhD, Michael Hooker Distinguished Professor of Protein Therapeutics and Translational Proteomics in the department of Pharmacology, who has a joint appointment at the UNC Eshelman School of Pharmacy.