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, according to the study's corresponding author Rajesh Khanna, a professor in the College of Medicine—Tucson's Department of Pharmacology.
"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 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."
The study will be published in PAIN, the journal of the International Association for the Study of Pain.
The US Centers for Disease Control and Prevention released updated data Sept. 10 estimating 50 percent of COVID-19 transmission occurs prior to the onset of symptoms and 40 percent of COVID-19 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 UArizona Health Sciences Senior Vice President Michael D. Dake.
Viruses infect host cells through protein receptors on cell membranes. Early in the pandemic, scientists established that the SARS-CoV-2 spike protein uses the angiotensin-converting enzyme 2 (ACE2) receptor to enter the body. But in June, two papers posted on the preprint server bioRxiv pointed to neuropilin-1 as a second receptor for SARS-CoV-2.
"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 affiliated with the UArizona Health Sciences Comprehensive Pain and Addiction Center and is a member of the UArizona BIO5 Institute. "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 a protein named vascular endothelial growth factor-A (VEGF-A), which 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. Dr. 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.
"Spike completely reversed the VEGF-induced pain signaling," Dr. Khanna said. "It didn't matter if we used very high doses of spike or extremely low doses—it reversed the pain completely."
