SARS-CoV-2, the virus that causes COVID-19, can relieve pain, according to a new study by University of Arizona (UArizona) Health Sciences researchers and published in the journal Pain.1,2

The finding has significance for two different reasons. First, it may explain why nearly half of all 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, PhD, a professor in the Department of Pharmacology at UArizona College of Medicine-Tucson.

Second, of most significant to the pain medicine and pain research community, is that the finding has prompted the investigators to begin studying whether neuropilin could lead to analgesic therapies.

"We are moving forward with designing small molecules against neuropilin, particularly natural compounds, that could be important for pain relief," Khanna said in a press release issued by UArizona Health Sciences.1

"We have a pandemic, and we have an opioid epidemic. They're colliding. Our findings have massive implications for both," Khanna continued. "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."

"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 Michael D. Dake, MD, senior vice president at UArizona Health Sciences, in a press release. "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."

The press release includes a link to a video describing the how the virus can block pain, and why the serendipitous discovery could lead to new analgesics.

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. In June o2020, 2 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 Khanna, who is affiliated with the UArizona Health Sciences Comprehensive Pain and Addiction Center and 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."

One of the biological pathways that signal the body to feel pain is through a protein, vascular endothelial growth factor-A (VEGF-A). VEGF-A 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.

"The spike protein completely reversed the VEGF-induced pain signaling," Khanna said in the press release. "It didn't matter if we used very high doses of spike or extremely low doses-it reversed the pain completely."

While immunologists and virologists continue to investigate the role of neuropilin in the spread of COVID-19, Khanna's lab will be examining neuropilin as a new target for nonopioid pain relief. During the study, Dr. 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.

Asymptomatic Transmission

Understanding more about asymptomatic transmission could be important to containing the virus. The global spread of SARS-CoV-2 continued unabated and even resurged in the US and other countries in the fall. Wearing of masks and social distancing is undermined when asymptomatic people are not motivated to comply, or become weary of using these preventive measures and question the need.

"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 Khanna in a press release from UArizona. "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."

Here is the article's abstract:

"Binding of SARS-CoV-2's Spike protein to host angiotensin converting enzyme 2 triggers viral entry, but other proteins may participate, including neuropilin-1 receptor (NRP-1). As both Spike protein and vascular endothelial growth factor-A (VEGF-A)-a pro-nociceptive and angiogenic factor, bind NRP-1, we tested if Spike could block VEGF-A/NRP-1 signaling. VEGF-A-triggered sensory neuronal firing was blocked by Spike protein and NRP-1 inhibitor EG00229. 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. A 'silencing' of pain via subversion of VEGF-A/NRP-1 signaling may underlie increased disease transmission in asymptomatic individuals."2

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