SARS-CoV-2 relieves pain, report scientists based at the University of Arizona Health Sciences, by acting on the VEGF-A/neuropilin signaling pathway. That is, the spike protein binds to the host cell’s neuropilin-1 receptor, preventing VEGF-A, or vascular endothelial growth factor-A, from doing the same. Thus blocked, VEGF-A cannot initiate a cascade of events that has been implicated in the hyperexcitability of neurons and, consequently, pain.

The scientists published their findings in a paper that appeared October 1 in the journal PAIN, in an article titled, “SARS-CoV-2 Spike protein co-opts VEGF-A/Neuropilin-1 receptor signaling to induce analgesia.” In their paper, the scientists suggested that their finding could explain why nearly half of people who get COVID-19 experience few or no symptoms, even though they are able to spread the disease.

According to the U.S. Centers for Disease Control and Prevention, 50% of COVID-19 transmission occurs prior to the onset of symptoms and 40% of COVID-19 infections are asymptomatic.

“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,” said Rajesh Khanna, PhD, the paper’s senior author and a professor of pharmacology at the College of Medicine, University of Arizona, Tucson. “You have the virus, but you don’t feel bad because your pain is gone. If we can prove that this pain relief is what is causing COVID-19 to spread further, that’s of enormous value.”

Besides suggesting how COVID-19 may be transmitted by people who lack symptoms, the new finding also suggests new approaches to pain relief. “[Our researchers] are leveraging this unique finding to explore a novel class of therapeutics for pain as we continue to seek new ways to address the opioid epidemic,” noted Michael D. Dake, MD, vice president, University of Arizona Health Sciences.

Possibilities for developing new pain relievers were also mentioned in the current paper. “We are specifically studying the downstream actions following the binding of VEGF-A165a to the b1 domain of NRP-1,” the paper’s authors wrote. “Targeting this interaction may be more specific compared to broad VEGF-A inhibitors that have been developed for cancer treatment. Thus, our preclinical work provides a rationale for targeting the VEGF-A/NRP-1 pronociceptive signaling axis in future clinical trials.”

The current paper also presented the line of inquiry that led to the new finding. The paper’s authors noticed that in June, two papers posted on the preprint server bioRxiv pointed to neuropilin-1 as a second receptor for SARS-CoV-2. (The first receptor, ACE2, or angiotensin-converting enzyme 2, had been identified early in the pandemic.)

“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 Khanna, who is affiliated with the University of Arizona Health Sciences Comprehensive Pain and Addiction Center. “So, we stepped back and realized this could mean that maybe the spike protein is involved in some sort of pain processing.”

Many biological pathways signal the body to feel pain. One is through VEGF-A, a protein that plays an essential role in blood vessel growth but also has 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 receptor neuropilin, it initiates a cascade of events resulting in the hyperexcitability of neurons, which leads to pain. Khanna and his research team found that the SARS-CoV-2 spike protein binds to neuropilin in exactly the same location as VEGF-A.

With that knowledge, they performed 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 neuron excitability, which creates pain, then added the SARS-CoV-2 spike protein.

“VEGF-A–triggered sensory neuronal firing was blocked by Spike protein and NRP-1 inhibitor EG00229,” the scientists indicated. “Pro-nociceptive behaviors of VEGF-A were similarly blocked via suppression of spontaneous spinal synaptic activity and reduction of electrogenic currents in sensory neurons. Remarkably, preventing VEGF-A/NRP-1 signaling was antiallodynic in a neuropathic pain model.”

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

Khanna is teaming up with University of Arizona Health Sciences immunologists and virologists to continue research into the role of neuropilin in the spread of COVID-19.

In his lab, he will be examining neuropilin as a new target for non-opioid pain relief. During the study, Khanna tested existing small molecule neuropilin inhibitors developed to suppress tumor growth in certain cancers and found they provided the same pain relief as the SARS-CoV-2 spike protein when binding to neuropilin.

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

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