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Principal Investigator: Rajesh Khanna
Organization: NEW YORK UNIVERSITY
Fiscal Year: 2023
Award: $95,887
Funding agency: National Institute of Neurological Disorders and Stroke
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 hypothesize that activation of the
VEGFA/NRP1/CRMP2/ion channel pathway elicits sensitization of dorsal root ganglion 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 anti-nociceptive effects of intrathecal NRP1inhibition mediated by targeting DRG
neurons, microglia, or both?
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.
Terms: <2019-nCoV S protein><2019-nCoV spike glycoprotein><2019-nCoV spike protein><21+ years old><A5 Antigen><Absence of pain sensation><Absence of sensibility to pain><Acute><Acute Pain><Adult><Adult Human><Affect><Affective><Afferent Neurons><Allergy><Analgesia Tests><Analgesic Agents><Analgesic Drugs><Analgesic Preparation><Analgesics><Angiogenesis Factor><Angiogenic Factor><Anodynes><Antinociceptive Agents><Antinociceptive Drugs><Assay><Attenuated><Behavior><Behavioral><Binding><Bioassay><Biochemical><Biologic Assays><Biological Assay><CNS Nervous System><COVID-19 S protein><COVID-19 spike glycoprotein><COVID-19 spike protein><COVID19 S protein><COVID19 spike glycoprotein><COVID19 spike protein><CRMP-2 protein><Calcium><Calcium Channel><Calcium Channel Antagonist Receptor><Calcium Channel Blocker Receptors><Calcium Ion Channels><Cell Communication and Signaling><Cell Signaling><Central Nervous System><Chemosensitization><Chemosensitization/Potentiation><Chronic><Clinical><Closure by Ligation><Common Rat Strains><Cytoplasm><Data><Development><Dorsal><Dorsal Root Ganglia><Feels no pain><Future><G Protein-Complex Receptor><G Protein-Coupled Receptor Genes><G-Protein-Coupled Receptors><GPCR><Genetic><Hortega cell><Human><Hypersensitivity><Intracellular Communication and Signaling><Intravenous><Ion Channel><Ionic Channels><KI mice><Kinases><Knock-in Mouse><Knock-out><Knockout><Ligation><Link><Maintenance><Malignant Pancreatic Neoplasm><Malignant neoplasm of pancreas><Mechanics><Mediating><Medulla Spinalis><Membrane Channels><Mice><Mice Mammals><Microglia><Modeling><Modern Man><Molecular><Molecular Interaction><Murine><Mus><NRP1 Protein><Nerve Cells><Nerve Impulse Transmission><Nerve Transmission><Nerve Unit><Neural Cell><Neuraxis><Neurocyte><Neuronal Transmission><Neurons><Neuropathy><Neuropilin-1><No sensitivity to pain><Nociception><Nociception Tests><Nociceptors><Npn-1 Protein><Pain><Pain Assessment><Pain Measurement><Painful><Pancreas Cancer><Pancreatic Cancer><Pathologic><Pathway interactions><Peripheral><Phosphorylation><Phosphotransferase Gene><Phosphotransferases><Potentiation><Protein Phosphorylation><Proteins><Publishing><Rat><Rats Mammals><Rattus><Receptor Protein><Receptor Signaling><Reporting><Resolution><Rodent><Rodent Model><Rodentia><Rodents Mammals><Role><SARS-CoV-2 S protein><SARS-CoV-2 spike glycoprotein><SARS-CoV-2 spike protein><SARS-CoV2 S protein><SARS-CoV2 spike glycoprotein><SARS-CoV2 spike protein><Sema III Receptor><Semaphorin III Receptor><Semaphorins><Sensory><Sensory Neurons><Severe acute respiratory syndrome coronavirus 2 S protein><Severe acute respiratory syndrome coronavirus 2 spike glycoprotein><Severe acute respiratory syndrome coronavirus 2 spike protein><Signal Induction><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Site><Sodium Channel><Sodium Ion Channels><Spinal><Spinal Column><Spinal Cord><Spinal Ganglia><Spinal Nerves><Spinal nerve structure><Spine><Stimulus><Surface><Synapses><Synaptic><Testing><Thermal Hyperalgesias><Transmission><Transphosphorylases><Traumatic Nerve Injury><VDCC><VEGF><VEGFA><VEGFA gene><VEGFs><Validation><Vascular Endothelial Cell Growth Factor 165 Receptor><Vascular Endothelial Growth Factor A><Vascular Endothelial Growth Factors><Vasculotropin><Vertebral column><Voltage-Dependent Calcium Channels><Work><adulthood><analgesia><animal pain><antagonism><antagonist><antinociception><antinociceptive><attenuate><attenuates><axon growth cone guidance><axon guidance><axon signaling><axon-glial signaling><axonal signaling><backbone><biological signal transduction><cancer pain><chronic neuropathic pain><chronic pain><chronic pain control><chronic pain intervention><chronic pain management><chronic pain therapy><chronic pain treatment><collapsin response mediator protein-2><coronavirus disease 2019 S protein><coronavirus disease 2019 spike glycoprotein><coronavirus disease 2019 spike protein><developmental><dorsal root ganglion><efficacy testing><efficacy validation><experiment><experimental research><experimental study><experiments><extracellular><gitter cell><glia signaling><glial signaling><humanized antibody><in vivo><inhibitor><knockin mice><mechanic><mechanical><mechanical allodynia><mesoglia><microglial cell><microgliocyte><nerve injury><nerve signaling><nervous system development><neural injury><neural signaling><neuronal><neuronal signaling><neuropathic><neuropathic pain><neurophysiological><neurophysiology><neurotransmission><neurotransmitter release><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><next generation><nociceptive><nociceptive neurons><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><pain assay><pain killer><pain medication><pain model><pain reduction><pain relief><pain reliever><pain-sensing neurons><pain-sensing sensory neurons><pain-sensing somatosensory neurons><painful neuropathy><painkiller><pancreatic malignancy><pathway><perivascular glial cell><pharmacologic><prevent><preventing><receptor><reduce pain><relieve pain><resolutions><response><sensor><social role><spared nerve><synapse><therapeutic target><trafficking><transmission process><treat chronic pain><validate efficacy><validations><voltage>