Why Do Some Opioid Drugs Cause Severe Itching?

Opioid drugs are commonly used for the treatment of pain. However, the side effects of these drugs may vary from addiction to respiratory failure and can even cause severe itching or dizziness. A research team from the University of North Carolina, is on the verge of finding out how opioid drugs cause side effects and how they can be avoided for better therapeutic results.

The study findings were published in the journal Nature Chemical Biology by the University of North Carolina School of Medicine.

The research team also found that MRGRPX2, a receptor protein on the surface of the mast cells, can now trigger an immune response which causes itching associated with opioids.

Kate Lansu, author and graduate student in the lab of Bryan Roth, MD, Ph.D, said, "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."

"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 are found to be linked with degranulation process, but there is also another unknown mechanism.The data has found how degranulation can occur as a side effect of opioid ligands; this is a well-known mechanism, although not well-understood.

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The research findings are significant as they revealed the potential explanation for opioid-induced itching, as well as suggested a way to characterize the function of an orphan receptor MRGRPX2.

There are about 120 orphan receptors in humans, and their functions are not well established. The Roth lab screens these receptors against a number of small molecules to find out how they are being activated. This process mainly involves a combination of physical screening and computational modeling.

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

"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."

About 3.7 million models were tested for potential interaction with receptors on computer modeling by a co-author Karpiak, graduate student at the University of California.

"And that's so much more different types of chemicals than I could do by hand in an assay," said Lansu.

The data collected when combined along with computational models may help the research team to create a probe which is designed to specifically interact with MRGRPX2.

The new tool may make it more precise to understand the receptor’s effects without the noise of other receptors. The opioids might activate the orphan receptor and also the other receptors which interact with it.

Lansu, explained this with an example of imagining to recreate a musical score by listening to a piece of music. But if you can find out a tool for isolating only the trumpets, it would be able to teach how the part contributes and something may not be able to hear it otherwise.

The research team also found that understanding the triggers for the itching response can help pharmacologists to develop an antagonist to reduce the itching side effect. The clinicians may also want to induce the histamine release and boost the immune response. This may occur in the case of vaccine adjuvants, where boosting the immune response may improve the immunity. The study findings found that there may be a way to do it selectively.

The research work may emphasize the importance of collaboration sciences as it includes computational modeling, pharmacologists, and chemists to make the necessary changes in the molecule. The people may work together and find out the possible mechanism behind opioid drugs.

Opioid Drugs
Opioid drugs include medications that relieve pain. Examples include oxycodone, hydrocodone, codeine or morphine.

These drugs may act on the opioid receptors present on the nerve cells in the brain and produce severe side effects.

Side Effects of Opioid Drugs

• Addiction
• Breathing difficulties
• Nausea
• Constipation
• Dizziness
• Itching

References

1. Katherine Lansu, Joel Karpiak, Jing Liu, Xi-Ping Huang, John D McCorvy, Wesley K Kroeze, Tao Che, Hiroshi Nagase, Frank I Carroll, Jian Jin, Brian K Shoichet, Bryan L Roth. In silico design of novel probes for the atypical opioid receptor MRGPRX2. Nature Chemical Biology, 2017; DOI: 10.1038/nchembio.2334
2. Opioid Addiction - ( http://www.asam.org/docs/default-source/advocacy/opioid-addiction-disease-facts-figures.pdf )
3. Opioids - (https://www.drugabuse.gov/drugs-abuse/opioids )

Source-Medindia