# Validation of Neuropilin-1 Receptor Signaling in Nociceptive Processing

> **NIH NIH RF1** · UNIVERSITY OF FLORIDA · 2023 · $1,926,350

## Abstract

ABSTRACT
Nociceptive pain is a protective response to harmful stimuli that is necessary to survival while nociplastic pain
represents altered nociception arising from a sensitization of peripheral nociceptor neurons leading
to subthreshold inputs eliciting a pain response. While studying a potential role for SARS-CoV-2 spike ^protein
in pain, we identified Neuropilin 1 (NRP1) as a key receptor mediating the transduction of vascular
endothelial growth factor-A (VEGFA) signaling to sensitize sensory neurons in models of nociplastic pain. In
models of nerve injury pain, vascular endothelial growth factor-A (VEGFA) – an angiogenic factor – binds
NRP1 and induces mechanical allodynia and thermal hyperalgesia. Pharmacological antagonism of NRP1
blocked VEGFA induced pain-like behaviors. This work demonstrated that NRP1 could be a novel therapeutic
target with the potential to reverse chronic pain. Mechanistically, NRP1 sits upstream of a cytosolic protein –
the collapsin response mediator protein 2 (CRMP2), a dual trafficking regulator of N-type voltage-gated calcium
(CaV2.2) as well as voltage-gated sodium channels. We hypothesized that activation of the
VEGFA/NRP1/CRMP2/ion channel pathway elicits sensitization of dorsal horn neurons,
consequently contributing to neuropathic pain states by enhancing excitatory synaptic input to dorsal
spinal cord neurons. In this proposal, we test the hypothesis that interfering with VEGFA binding to
NRP1 initiates an intracellular signaling cascade that, through CRMP2, leads to a decrease in sodium
and calcium channel functional activity to decrease nociceptor activity culminating in reduced pain-like
behaviors. We plan to test our hypothesis by using two chronic pain models to answer the following questions:
 1. Does NRP1 signaling induce nociceptor sensitization and chronic hypersensitivity via
CRMP2?
 2. How does NRP1 signaling affect acute and chronic pain?
 3. Are the behavioral effects of NRP1 mediated by neurons or microglia in the DRG?
Completion of the proposed studies will allow: (i) validation of a novel target of chronic pain, (ii) use two chronic
pain models to explore the breadth of applicability, and (iii) provide important information for development of a
next generation of mechanism-based chronic pain medications.
Overall, completion of these experiments will validate the role of NRP1 in nociceptive processing and will open
opportunities for future therapeutic targeting of NRP1 for chronic pain treatment.

## Key facts

- **NIH application ID:** 11138856
- **Project number:** 7RF1NS131165-02
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Rajesh Khanna
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $1,926,350
- **Award type:** 7
- **Project period:** 2024-01-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11138856

## Citation

> US National Institutes of Health, RePORTER application 11138856, Validation of Neuropilin-1 Receptor Signaling in Nociceptive Processing (7RF1NS131165-02). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/11138856. Licensed CC0.

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