Abstract
Global spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues unabated. 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.
Competing Interest Statement
R. Khanna is the co-founder of Regulonix LLC, a company developing non-opioids drugs for chronic pain. In addition, R. Khanna has patents US10287334 and US10441586 issued to Regulonix LLC. The other authors declare no competing financial interests.
Footnotes
New results show that VEGF-A facilitation of mechanical allodynia and thermal hyperalgesia is also seen in female rats and this is blocked by Spike and NRP-1 inhibition with EG00229 (Figure 2). Neither Spike or EG00229 alone affect spinal neurotransmission (Figure 5). Spike, in a dose-dependent manner, reverses mechanical allodynia in the SNI model of neuropathic pain (Figure 6).
ABBREVIATIONS USED
- ACE2
- Angiotensin converting enzyme 2
- AUC
- area under the curve
- CaV2.2
- N-type voltagegated calcium channel
- COVID-19
- coronavirus disease 2019
- DRG
- dorsal root ganglia
- MEA
- multi-well microelectrode array
- NaV1.7
- voltage-gated sodium channel isoform 7
- NRP-1
- Neuropilin-1
- PWTs
- paw withdrawal thresholds
- RBD
- receptor binding domain
- SARS-CoV-2
- Severe acute respiratory syndrome coronavirus 2
- sEPSCs
- spontaneous excitatory postsynaptic currents
- SNI
- spared nerve injury
- VEGF-A
- vascular endothelial growth factor-A