COVID-19 could provide a new target for non-opioid pain relief according to new research, which has found that the virus can relieve pain.
The findings from the University of Arizona Health Sciences researchers could explain why almost 50% of people who contract the virus experience no, or limited, symptoms. They also suggest this could explain why the virus is spread so easily.
The paper, ‘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.
Pain relief contributes to COVID-19 spread
According to the US 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.
Viruses infect host cells through protein receptors on cell membranes, and early on in the pandemic, scientists established that the SARS-CoV-2 spike protein uses the angiotensin-converting enzyme 2 (ACE2) receptor to enter the body. Later in June, two further papers pointed to neuropilin-1 as a second receptor for SARS-CoV-2.
Corresponding author, Rajesh Khanna, PhD, a professor in the College of Medicine – Tucson’s Department of Pharmacology, said: “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. 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.”
“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 signalling pathways,” said University of Arizona Health Sciences Senior Vice President Michael 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.”
Dr Khanna added: “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. So, we stepped back and realised this could mean that maybe the spike protein is involved in some sort of pain processing.”
A new, novel class of pain therapeutics?
One biological pathway that signals the body to feel pain 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.
VEGF-A binds to the receptor neuropilin causing events that result 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.
The researchers used animal models to test the hypothesis that the SARS-CoV-2 spike protein acts on the VEGF-A/neuropilin pain pathway, using VEGF-A as a trigger to induce neuron excitability, which creates pain, then added the SARS-CoV-2 spike protein.
Dr Khanna said: “Spike completely reversed the VEGF-induced pain signalling. It didn’t matter if we used very high doses of spike or extremely low doses – it reversed the pain completely.”
Dr 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 and will be examining neuropilin as a new target for non-opioid pain relief.
“We are moving forward with designing small molecules against neuropilin, particularly natural compounds, that could be important for pain relief,” he 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.”