A new study that researchers conducted in animal models suggests that SARS-CoV-2, the virus that causes COVID-19, may deactivate a pain signaling pathway. This could explain why so many cases of the infection do not cause any symptoms, promoting viral transmission.

Estimates vary widely, but according to the Centers for Disease Control and Prevention’s (CDC) current best estimates, 40% of people with COVID-19 may experience no symptoms.

These people may carry on with their daily activities as usual, without necessarily realizing that they have contracted the virus. This may cause them to spread it unintentionally. For this reason, some scientists refer to people without symptoms as “silent spreaders.”

The CDC also estimate that up to 50% of all SARS-CoV-2 transmission occurs before the onset of symptoms.

Stay informed with live updates on the current COVID-19 outbreak and visit our coronavirus hub for more advice on prevention and treatment.

One recent study provides a possible explanation for asymptomatic cases and the lack of symptoms early in the course of more serious infections.

SARS-CoV-2 gains entry to its host cells via a receptor in their outer membrane called ACE2. The spike proteins that give the coronavirus its characteristic crown-like appearance latch onto these receptors.

However, the virus can also invade cells when its spikes bind to another membrane receptor called neuropilin.

This receptor’s usual binding partner is called vascular endothelial growth factor A (VEGF-A), which, among other things, promotes the growth of blood vessels.

Crucially, when VEGF-A binds to neuropilin, it also stimulates a pain signaling pathway in the nervous system.

Researchers at the University of Arizona in Tucson have now discovered that the spike protein of SARS-CoV-2 blocks these pain pathways when it locks onto neuropilin.

This suggests that the virus numbs the pain of infection, possibly to the extent that people feel few, if any, symptoms early in the disease.

The findings of this study appear in the journal Pain.

Feeling fine

“It made a lot of sense to me that perhaps the reason for the unrelenting spread of COVID-19 is that in the early stages, you’re walking around all fine as if nothing is wrong because your pain has been suppressed,” says corresponding study author Rajesh Khanna, a professor in the Department of Pharmacology at the University of Arizona College of Medicine.

“You have the virus, but you don’t feel bad because your pain is gone,” he adds. “If we can prove that this pain relief is what is causing COVID-19 to spread further, that’s of enormous value.”

Using cell cultures grown in the laboratory, the scientists showed that when VEGF-A binds to neuropilin in the membranes of rat sensory nerve cells, their firing rate increases.

When the researchers added spike proteins from SARS-CoV-2 to the culture medium, it prevented VEGF-A from stimulating the nerve cells.

Next, they demonstrated that injecting rats with VEGF-A increased the animals’ pain sensitivity. However, when they added the viral spike protein to the injected solution, the rats’ pain sensitivity remained at normal levels.

“The spike protein completely reversed the VEGF-induced pain signaling,” says Prof. Khanna. “It didn’t matter if we used very high doses of spike or extremely low doses — it reversed the pain completely.”

Opioid substitutes

For the past 15 years, Prof. Khanna’s team has been studying the neuropilin pain pathway with a view to developing substitutes for opioid drugs. Many people blame these drugs for an epidemic of addiction.

“We are moving forward with designing small molecules against neuropilin, particularly natural compounds, that could be important for pain relief,” explains Prof. Khanna.

“We have a pandemic, and we have an opioid epidemic. They’re colliding. Our 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.”

– Prof. Rajesh Khanna

It is important to note, however, that the new study was laboratory-based. Therefore, it was unable to prove whether or not inhibiting the neuropilin pain pathway plays a significant role in humans with COVID-19.

Interestingly, scientists already know a lot about VEGF-A because of its role in promoting blood vessel growth, or angiogenesis, in cancer. Scientists have developed drugs that prevent VEGF-A from binding to neuropilin, such as Avastin, as anticancer treatments.

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