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SARS-CoV-2, the virus that causes COVID-19, may ease pain, according to a new study by University of Arizona Health Sciences researchers.
The finding may explain why nearly half of people who contract COVID-19 experience few or no symptoms, even though they can spread the disease, according to the study’s corresponding author, Rajesh Khanna, PhD, a professor at the School of Medicine. from Tucson. Department of Pharmacology.
“It made perfect sense to me that perhaps the reason for the relentless spread of COVID-19 is that in the early stages, you are walking 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 the pain is gone. If we can show that this pain relief is what is causing COVID-19 to spread the most, that is of enormous value.”
The article, “SARS-CoV-2 Spike Protein Co-opts VEGF-A / Neuropilin-1 Receptor Signaling to Induce Analgesia”, will be published in PAIN, the journal of the International Association for the Study of Pain.
The U.S. Centers for Disease Control and Prevention released updated data on September 10 that estimates that 50% of COVID-19 transmission occurs before the onset of symptoms and 40% of COVID-19 infections. COVID-19 are asymptomatic.
“This research raises the possibility that pain, as an early symptom of COVID-19, may be reduced by the spike protein SARS-CoV-2 as it silences the body’s pain signaling pathways,” said Senior Vice President of UA Arizona Health Sciences, Michael D. Dake, MD. “University of Arizona Health Sciences researchers at the Comprehensive Center for Pain and Addiction are leveraging this unique finding to explore a new class of pain therapies as we continue to seek new ways to address the opioid epidemic.” .
Viruses infect host cells through protein receptors on cell membranes. At the beginning of 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 articles published on the bioRxiv preprint server pointed to neuropilin-1 as a second receptor for SARS-CoV-2.
“That caught our attention because for the past 15 years my lab has been studying a complex of proteins and pathways that are related to pain processing that are posterior to neuropilin,” said UArizona Health Sciences affiliate Dr. Khanna Comprehensive Pain and Addiction Center and is a member of the UArizona BIO5 Institute. “So we took a step back and realized that this could mean that maybe the spike protein is involved in some kind of pain processing.”
Many biological pathways tell the body to feel pain. One is through a protein called vascular endothelial growth factor A (VEGF-A), which plays an essential role in the growth of blood vessels, but has also been linked to diseases such as cancer, rheumatoid arthritis, and more recently, COVID-19.
Like a key in a lock, when VEGF-A binds to the neuropilin receptor, it initiates a cascade of events that results in the hyperexcitability of neurons, leading to pain. Dr. Khanna and his research team discovered that the SARS-CoV-2 spike protein binds to neuropilin in exactly the same location as VEGF-A.
With that knowledge, they conducted 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 excitability of neurons, which creates pain, then added the SARS-CoV-2 spike protein.
“Spike completely reversed VEGF-induced pain signaling,” Dr. Khanna said. “It didn’t matter if we used very high spike doses or extremely low doses, the pain was completely reversed.”
Dr. Khanna is partnering with immunologists and virologists from UArizona Health Sciences to continue research on the role of neuropilin in the spread of COVID-19.
In his lab, he will examine neuropilin as a new target for non-opioid pain relief. During the study, Dr. Khanna tested existing small molecule neuropilin inhibitors developed to suppress tumor growth in certain cancers and found that they provided the same pain relief as the SARS-CoV-2 spike protein when it binds to the neuropilin.
“We are advancing the design of small molecules against neuropilin, in particular natural compounds, that could be important in relieving pain,” said Dr. Khanna. “We have a pandemic and an opioid epidemic. They are colliding. Our findings have massive implications for both. SARS-CoV-2 is teaching us about viral spread, but COVID-19 also makes us see neuropilin as a new method without opioids to combat the opioid epidemic. “
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Co-authors of the article from the Department of Pharmacology are: Aubin Moutal, PhD; Lisa Boinon; Kimberly Gomez, PhD; Dongzhi Ran, PhD; Yuan Zhou; Harrison Stratton, PhD; Song Cai, PhD; Shizhen Luo; Kerry Beth González; and Samantha Perez-Miller, PhD. Co-authors from the Department of Anesthesiology with additional affiliations with the Comprehensive Center for Pain and Addiction are Amol Patwardhan, MD, PhD and Mohab Ibrahim, MD, PhD.
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