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Pain relief caused by SARS-CoV-2 infection may help explain COVID-19 spread

PhD student Lisa Boinon prepares buffers while Dr. Rajesh Khanna is watching. Photo credit: University of Arizona Health Sciences, Kris Hanning

SARS-CoV-2, the virus that causes COVID-19, may relieve pain, according to a new study by researchers at the University of Arizona Health Sciences.

The finding could explain why nearly half of the people who get COVID-19 have few or no symptoms despite being able to spread the disease, according to the study's lead author, Rajesh Khanna, Ph. D., Professor in the College of Medicine – Tucson's Department of Pharmacology.

"It made a lot of sense to me that maybe the reason the relentless spread of COVID-19 is because you walk around well in the early stages as if nothing was wrong because your pain has been suppressed," said Dr. Khanna. "You have the virus, but you don't feel bad because your pain is gone. If we can prove that this pain relief is causing COVID-19 to continue to spread, it will be of tremendous value."

The paper "SARS-CoV-2 spike protein co-opts VEGF-A / Neuropilin-1 receptor signals to induce analgesia" is published in PAIN, the journal of the International Association for the Study of Pain.

The U.S. Centers for Disease Control and Prevention released updated data on Sept. 10 that 50% of COVID-19 transmission occurs before symptoms appear and 40% of COVID-19 infections are asymptomatic.

"This research opens up the possibility that pain, an early symptom of COVID-19, may be reduced by the SARS-CoV-2 spike protein as it silences the body's pain pathways," said Michael D., senior vice president from UArizona Health Sciences. Dake, MD. "Researchers at the University of Arizona Health Sciences at the Comprehensive Pain and Addiction Center are leveraging this unique insight to explore a novel class of pain relievers as we continue to explore new ways to fight the opioid epidemic."

Viruses infect host cells through protein receptors on cell membranes. At the start of the pandemic, scientists discovered that the SARS-CoV-2 spike protein uses the angiotensin converting enzyme-2 receptor (ACE2) to enter the body. In June, two articles published on the preprint server bioRxiv pointed to Neuropilin-1 as the second receptor for SARS-CoV-2.

"We noticed this because my lab has been studying a complex of proteins and pathways related to pain processing that are downstream of neuropilin for the past 15 years," said Dr. Khanna is a member of the UArizona Health Sciences Comprehensive Pain and Addiction Center and is a member of the UArizona BIO5 Institute. "So we stepped back and realized that this could mean that the spike protein may be involved in some kind of pain processing."

There are many biological pathways that signal the body to feel pain. One of them is a protein called vascular endothelial growth factor A (VEGF-A), which plays an essential role in blood vessel growth but has also been linked to diseases such as cancer, rheumatoid arthritis, and most recently COVID-19.

Like a key in a lock, when VEGF-A binds to the neuropilin receptor, it triggers a cascade of events that lead to over-excitability of neurons, resulting in pain. Dr. Khanna and his research team found that the SARS-CoV-2 spike protein binds to Neuropilin in exactly the same place as VEGF-A.

An animated look at the science of how SARS-CoV-2 infection induces analgesia. Photo credit: University of Arizona Health Sciences / Debra Bowles

With this knowledge, they conducted a series of experiments in the laboratory and in rodent models to test their hypothesis that the SARS-CoV-2 spike protein acts on the VEGF-A / Neuropilin pain pathway. They used VEGF-A as a trigger to induce the excitability of neurons that causes pain, and then added the SARS-CoV-2 spike protein.

"The spike protein completely reversed the VEGF-induced pain signal," said Dr. Khanna. "It didn't matter if we used very high or extremely low doses of spikes – it completely reversed the pain."

Dr. Khanna is working with immunologists and virologists from UArizona Health Sciences to further research the role of Neuropilin in the spread of COVID-19.

In his lab, he will study Neuropilin as a new target for pain relief without opioids. During the study, Dr. Khanna present small molecule neuropilin inhibitors, which are designed to suppress tumor growth in certain types of cancer, and found that when bound to neuropilin, they provide the same pain relief as the SARS-CoV-2 spike protein.

"We're developing small molecules against neuropilin, especially natural compounds that may be important in pain relief," said Dr. Khanna. "We have a pandemic and we have an opioid epidemic. They collide. Our findings have massive implications for both of them. SARS-CoV-2 teaches us about the spread of viruses, but COVID-19 also leaves us with Neuropilin as a new non-opioid -Method of Combating the Opioid Epidemic. "

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More information:
Aubin Moutal et al. The SARS-CoV-2 spike protein co-opts the VEGF-A / Neuropilin-1 receptor signal to induce analgesia, Pain (2020). DOI: 10.1097 / j.pain.0000000000002097

Journal information:

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University of Arizona

Relief of pain caused by SARS-CoV-2 infection may help explain the spread of COVID-19 (2020, October 1).
accessed on October 1, 2020

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