Analysis reveals SARS-CoV-2 promotes ache aid by the receptor neuropilin-1, which supplies scientists a brand new goal for non-opioid ache therapeutics and provides one doable rationalization for the unrelenting unfold of COVID-19.
SARS-CoV-2, the virus that causes COVID-19, can relieve ache, in response to a brand new research by College of Arizona Well being Sciences researchers.
The discovering could clarify why almost half of all individuals who get COVID-19 expertise few or no signs, though they’re able to unfold the illness, in response to the research’s corresponding writer Rajesh Khanna, PhD, a professor within the UArizona Faculty of Drugs – Tucson’s Division of Pharmacology.
“It made lots of sense to me that maybe the rationale for the unrelenting unfold of COVID-19 is that within the early phases, you’re strolling round all high quality as if nothing is fallacious as a result of your ache has been suppressed,” mentioned Dr. Khanna. “You’ve gotten the virus, however you don’t really feel unhealthy as a result of your ache is gone. If we are able to show that this ache aid is what’s inflicting COVID-19 to unfold additional, that’s of huge worth.”
An animated video of how SARS-CoV-2 reduces ache.
The paper, “SARS-CoV-2 Spike protein co-opts VEGF-A/Neuropilin-1 receptor signaling to induce analgesia,” was printed lately in PAIN, the journal of the Worldwide Affiliation for the Research of Ache.
The U.S. Facilities for Illness Management and Prevention launched up to date information Sept. 10 estimating that fifty% of COVID-19 transmission happens previous to the onset of signs and 40% of COVID-19 infections are asymptomatic.
“This analysis raises the chance that ache, as an early symptom of COVID-19, could also be diminished by the SARS-CoV-2 spike protein because it silences the physique’s ache signaling pathways,” mentioned UArizona Well being Sciences Senior Vice President Michael D. Dake, MD. “College of Arizona Well being Sciences researchers on the Complete Ache and Dependancy Middle are leveraging this distinctive discovering to discover a novel class of therapeutics for ache as we proceed to hunt new methods to deal with the opioid epidemic.”
Dr. Rajesh Khanna explaining how his crew recognized the phenomenon of SARS-CoV-2 lowering ache.
Viruses infect host cells by protein receptors on cell membranes. Early within the pandemic, scientists established that the SARS-CoV-2 spike protein makes use of the angiotensin-converting enzyme 2 (ACE2) receptor to enter the physique. However in June, two papers posted on the preprint server bioRxiv pointed to neuropilin-1 as a second receptor for SARS-CoV-2.
“That caught our eye as a result of for the final 15 years my lab has been finding out a fancy of proteins and pathways that relate to ache processing which are downstream of neuropilin,” mentioned Dr. Khanna, who’s affiliated with the UArizona Well being Sciences Complete Ache and Dependancy Middle and a member of the UArizona BIO5 Institute. “So we stepped again and realized this might imply that possibly the spike protein is concerned in some kind of ache processing.”
Many organic pathways sign the physique to really feel ache. One is thru a protein named vascular endothelial development factor-A (VEGF-A), which performs a vital function in blood vessel development but additionally has been linked to ailments corresponding to most cancers, rheumatoid arthritis and, most lately, COVID-19.
Like a key in a lock, when VEGF-A binds to the receptor neuropilin, it initiates a cascade of occasions ensuing within the hyperexcitability of neurons, which ends up in ache. Dr. Khanna and his analysis crew discovered that the SARS-CoV-2 spike protein binds to neuropilin in precisely the identical location as VEGF-A.
See a 3D rendering of neuropilin with VEGF-A (left), spike protein (center) and small molecule inhibitor (proper) within the binding pocket right here:
With that data, they carried out a collection of experiments within the laboratory and in rodent fashions to check their speculation that the SARS-CoV-2 spike protein acts on the VEGF-A/neuropilin ache pathway. They used VEGF-A as a set off to induce neuron excitability, which creates ache, then added the SARS-CoV-2 spike protein.
“The spike protein utterly reversed the VEGF-induced ache signaling,” Dr. Khanna mentioned. “It didn’t matter if we used very excessive doses of spike or extraordinarily low doses – it reversed the ache utterly.”
Dr. Khanna is teaming up with UArizona Well being Sciences immunologists and virologists to proceed analysis into the function of neuropilin within the unfold of COVID-19.
In his lab, he will likely be inspecting neuropilin as a brand new goal for non-opioid ache aid. In the course of the research, Dr. Khanna examined current small molecule neuropilin inhibitors developed to suppress tumor development in sure cancers and located they supplied the identical ache aid because the SARS-CoV-2 spike protein when binding to neuropilin.
“We’re shifting ahead with designing small molecules in opposition to neuropilin, notably pure compounds, that may very well be vital for ache aid,” Dr. Khanna mentioned. “We now have a pandemic, and now we have an opioid epidemic. They’re colliding. Our findings have huge implications for each. SARS-CoV-2 is instructing us about viral unfold, however COVID-19 has us additionally neuropilin as a brand new non-opioid technique to combat the opioid epidemic.”
Reference: “SARS-CoV-2 Spike protein co-opts VEGF-A/Neuropilin-1 receptor signaling to induce analgesia” by Moutal, Aubin; Martin, Laurent F.; Boinon, Lisa; Gomez, Kimberly; Ran, Dongzhi; Zhou, Yuan; Stratton, Harrison J.; Cai, Tune; Luo, Shizhen; Gonzalez, Kerry Beth; Perez-Miller, Samantha; Patwardhan, Amol; Ibrahim, Mohab M. and Khanna, Rajesh, 1 October 2020, Ache.
Co-authors on the paper from the Division of Pharmacology are: Aubin Moutal, PhD; Lisa Boinon; Kimberly Gomez, PhD; Dongzhi Ran, PhD; Yuan Zhou; Harrison Stratton, PhD; Tune Cai, PhD; Shizhen Luo; Kerry Beth Gonzalez; and Samantha Perez-Miller, PhD. Co-authors from the Division of Anesthesiology, with extra affiliations with the Complete Ache and Dependancy Middle, are Amol Patwardhan, MD, PhD, and Mohab Ibrahim, MD, PhD.
This analysis was funded by the Nationwide Institute of Neurological Problems and Stroke, a unit of the Nationwide Institutes of Well being (NIH), beneath Award No. NS098772; and the Nationwide Institute on Drug Abuse, additionally an NIH unit, beneath Award No. DA042852.