COVID-19 Protein Provides Pain Relief, Opening Up Targets for Future Pain Treatments What are the main findings?

Response: The surprise discovery that Spike protein, the major cell surface protein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is analgesic means that asymptomatic and presymptomatic individuals may unwittingly spread the virus widely through human populations. We show that the Spike protein induces pain relief via binding to a surface receptor (neuropilin 1, NRP-1) on host cells. This study explored the novel concept that the SARS-CoV-2 Spike protein hijacks neuropilin 1 receptor (NRP-1) signaling to ameliorate VEGF-A-triggered pain. This raises the possibility that pain, as an early symptom of COVID-19, may be directly dampened by the SARS-CoV-2 Spike protein. What should readers take away from your report?

Response: First, our data shows that the Spike protein of SARS-CoV-2 is analgesic through subversion of a signaling pathway involving vascular endothelial growth factor-A (VEGF-A) and a host surface receptor (neuropilin-1). Our work shows that Spike protein essentially ‘silences’ the pain in asymptomatic or mildly symptomatic individuals which may contribute to the increased disease transmission.

COVID-19  SPIKE protein induces pain relief.
photo credit- Kris Hanning
COVID-19 SPIKE protein induces pain relief.
photo credit- Kris Hanning

Second, Spike’s analgesic activity occur via the neuropilin 1 receptor, which had not been previously linked to pain. Thus, our work opens up opportunities for future therapeutic targeting of neuropilin 1 receptor for persistent neuropathic pain treatments.

Third, prior to the ‘surprise’ emergence of the COVID-19 pandemic in December 2019, the United States and parts of the World were mired by the opioid epidemic. Emerging data suggest that the COVID-19 pandemic is likely to compound the opioid epidemic, which makes the findings presented here relevant to two current global health crises. What recommendations do you have for future research as a result of this work?

Response: For the pain field, the implications are the recognition and characterization of the role of neuropilin 1 receptor as a new player in pain. These findings may lead to kickstarting the discovery of a novel class of therapeutics for pain based on leveraging the atypical anti-pain function of SARS-CoV-2 Spike protein. Is there anything else you would like to add?

Response: Our data shows reversal of injury induced pain in rats. This injury models a form of neuropathic (persistent) pain. Whether Spike protein can reverse other kinds of pain (eg. Arthritic, cancer induced, inflammation, surgical etc) is too early to tell.  But we are currently investigating targeting of neuropilin-1, the new target of pain revealed by our current study, for potential utility for developing a new class of anti-pain drugs.

A limitation in our study is that while we looked at the effect of Spike directly on pain, patients also develop an immune response neutralizing the virus – we did not test if this happened in our rats. We have anecdotal evidence from chronic pain patients emailing us reporting that their pain is gone when they contracted COVID.

COI disclosures are all in Pain publication.

Citation: Moutal, Aubin1; Martin, Laurent F.2,†; Boinon, Lisa1,†; Gomez, Kimberly1,†; Ran, Dongzhi1,†; Zhou, Yuan1,†; Stratton, Harrison J.1; Cai, Song1; Luo, Shizhen1; Gonzalez, Kerry Beth1; Perez-Miller, Samantha1,2; Patwardhan, Amol1,2,4; Ibrahim, Mohab M.1,2,4; Khanna, Rajesh1,2,3,4,* SARS-CoV-2 Spike protein co-opts VEGF-A/Neuropilin-1 receptor signaling to induce analgesia, PAIN: October 01, 2020 – Volume Articles in Press – Issue – doi: 10.1097/j.pain.0000000000002097

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