The virus that causes COVID-19 inhibits a pain signaling pathway in the body, according to a new study from the University of Arizona. The discovery was made after researchers identified a second protein receptor, neuropilin, that is used by SARS-COV-2 to gain entry into cells.
Study co-author Dr. Rajesh Khanna is a professor in the College of Medicine at Tucson’s Department of Pharmacology. He said the fact that SARS-COV-2 relieves pain 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.
“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 Dr. Khanna. “You have the virus, but you don’t feel bad because you 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.”
On September 10, the CDC released updated data on COVID-19 which estimates that 50 percent of transmission occurs prior to the onset of symptoms and 40 percent of infections are asymptomatic.
“This research raises the possibility that pain, as an early symptom of COVID-19, may be reduced by the SARS-CoV-2 spike protein as it silences the body’s pain signaling pathways,” said Dr. Michael D. Dake. “University of Arizona Health Sciences researchers at the Comprehensive Pain and Addiction Center 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.”
Scientists established early on in the pandemic that the SARS-CoV-2 spike protein uses ACE2 receptors located on cell membranes to enter the body. In June, two studies identified a second receptor for the SARS-COV-2 spike protein called neuropilin-1, which is active in nerve cells.
“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 Dr. Khanna, who is an expert in the UArizona 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.”
There are different biological pathways that signal the body to feel pain, and one such pathway involves a protein called vascular endothelial growth factor-A (VEGF-A). This protein plays an essential role in blood vessel growth but also has been linked to diseases such as cancer and rheumatoid arthritis.
The researchers explained that VEGF-A binds to the receptor neuropilin like a key in a lock, triggering a series of events that causes an excessive reaction in neurons and initiates pain transmission. Dr. Khanna and his team found that the SARS-CoV-2 spike protein binds to neuropilin in exactly the same location as VEGF-A.
Using mouse models, the experts conducted experients to investigate whether the SARS-CoV-2 spike protein acts on the VEGF-A/neuropilin pain pathway. The researchers used VEGF-A as a trigger to induce neuron excitability and pain transmission – then added the SARS-CoV-2 spike protein.
“Spike completely reversed the VEGF-induced pain signaling,” said Dr. Khanna. “It didn’t matter if we used very high doses of spike or extremely low doses – it reversed the pain completely.”
Dr. Khanna will continue to investigate neuropilin’s role in the spread of COVID-19 with UArizona Health Sciences immunologists and virologists. The experts are also exploring the potential for neuropilin to be used as a target for non-opioid pain relief.
While conducting various trials, Dr. Khanna tested small molecule neuropilin inhibitors that are designed to suppress tumor growth in certain cancers. The small molecule inhibitors provided the same pain relief as the SARS-CoV-2 spike protein when binding to neuropilin receptors.
“We are moving forward with designing small molecules against neuropilin, particularly natural compounds, that could be important for pain relief,” said Dr. 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.”
The study is published in the journal Pain.