Pain relief caused by SARS-CoV-2 infection may help explain
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SARS-CoV-2, the virus that causes COVID-19, can relieve pain, according to a new study by University of Arizona Health Sciences researchers.

The finding may explain why nearly half of people who get COVID-19 experience few or no symptoms, even though they are able to spread the disease, said researchers.

Early in the pandemic, scientists established that the novel coronavirus SARS-CoV-2 spike protein uses the human cells' angiotensin-converting enzyme 2 (ACE2) receptor to enter the body.

Later in June, two studies published in the preprint server bioRxiv pointed to neuropilin-1 as a second receptor for SARS-CoV-2, the researchers said.

"That caught our eye because for the last 15 years my lab has been studying a complex of proteins and pathways that relate to pain processing that are downstream of neuropilin," said researchers. "So we stepped back and realized this could mean that maybe the spike protein is involved in some sort of pain processing".

One of the biological pathways signal through which the body feels pain is via a protein named vascular endothelial growth factor-A (VEGF-A) that plays an essential role in blood vessel growth but also has been linked to diseases such as cancer, and rheumatoid arthritis, the scientists said.

They added that most recently this protein has been linked to COVID-19. Like a key in a lock, when VEGF-A binds to the receptor neuropilin, it initiates a cascade of events resulting in the hyperexcitability of neurons, which leads to pain, the study noted. The team found that the SARS-CoV-2 spike protein binds to neuropilin in exactly the same location as VEGF-A.

They performed a series of lab experiments, and in rodent models to test their hypothesis that the SARS-CoV-2 spike protein acts on the VEGF-A/neuropilin pain pathway.

The researchers used VEGF-A as a trigger to induce excitation of nerve cells which create pain, then added the SARS-CoV-2 spike protein.

"Spike completely reversed the VEGF-induced pain signaling. It didn't matter if we used very high doses of spike or extremely low doses -- it reversed the pain completely," researchers said.

The scientists further examined neuropilin as a new target for non-opioid pain relief. During the study, they tested existing small molecule neuropilin inhibitors developed to suppress tumour growth in certain cancers and found they provided the same pain relief as the SARS-CoV-2 spike protein when binding to neuropilin.

"We have a pandemic, and we have an opioid epidemic. They're colliding. These findings have massive implications for both. SARS-CoV-2 is teaching us about viral spread, but COVID-19 has us also looking at neuropilin as a new non-opioid method to fight the opioid epidemic," researchers added.

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