Discovering the Role of the Neuropilin Pain Pathway in Asymptomatic COVID-19 Cases

Aditi Kaveti ’23

Figure 1: The SARS-CoV-2 pathogen binds to the neuropilin receptor and is involved in pain suppression in COVID-19.

In the United States, there have been more than 7 million documented cases of COVID-19, leading to over 200,000 deaths nationwide. This high number of cases is due to the rapid spread of the deadly disease, which is caused by a virus called SARS-CoV-2. Many researchers believe that the rapid spread can be in part attributed to a high number of asymptomatic patients unwittingly transporting the pathogen. In fact, the United States Center for Disease Control and Prevention has released data estimating about 40% of COVID-19 patients to be asymptomatic. 

Dr. Rajesh Khanna may have some answers as to why the virus can frequently present without any symptoms. Dr. Khanna, a professor of pharmacology at the University of Arizona’s College of Medicine, studies a complex of proteins and pathways that relate to pain processing. These pathways are controlled by the activation of the receptor called neuropilin. When the vascular endothelial growth-factor A (VEGF-A) protein binds to the neuropilin, it commences a cascade of biochemical events which makes neurons very hyperexcitable, or sensitive, causing a response of pain in the organism. In June, two papers posted in bioRxiv pointed to neuropilin-1 as a receptor for SARS-CoV-2. Using these studies, Dr. Khanna and his team hypothesized that a spike protein on the pathogen binds to neuropilin in the same location as VEFG-A, thus inducing neuron excitability in the VEGF-A/neuropilin pathway. The spike protein was theorized as the culpable factor, as it remains the sole viral membrane protein responsible for cell entry, often used to bind to the receptor on the target cell and induce specialized cell responses. 

The team combined laboratory experiments and rodent models to test their hypothesis. Using pathogen-free adult Sprague-Dawley rats, researchers triggered the neuropilin pathway with VEGF-A before administering the SARS-Co-V-2 S protein through intrathecal cannulation. This technique allows for necessary administration of the agent locally onto the spinal cord without causing untoward spinal effects. The team found that the SARS CoV-2 spike protein completely reverses the signaling performed by VEGF-A in the neuropilin pain pathway and prevents a pain response, no matter how much or how little of the SARS CoV-2 protein was used. Dr. Khanna and his colleagues look forward to examining the possibilities of their discovery with not only with regards to the spread of COVID-19 but also from an opioid alternative and pain relief viewpoint.

Works Cited:

[1] Works Cited:University of Arizona Health Sciences, Pain relief caused by SARS-CoV-2 infection may help explain COVID-19 spread. ScienceDaily, (2020).

[2] A. Moutal, et al. SARS-CoV-2 spike protein co-opts VEGF-A/Neuropilin-1 receptor signaling to induce analgesia. PAIN (2020). doi: 10.1097/j.pain.0000000000002097

[3] Image retrieved from:


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