# Genetic and Pharmacological Validation of CRMP2 Phosphorylation as a Novel therapeutic Target for Neuropathic Pain

> **NIH NIH R01** · NEW YORK UNIVERSITY · 2020 · $796,630

## Abstract

SUMMARY
Effective treatment of high-impact pain patients is one of the major stated goals of the National Pain
Strategy. Identification of new targets and mechanisms underlying neuropathic pain will be critical in
developing new target-specific medications for better neuropathic pain management. We recently
discovered that peripheral nerve injury-induced upregulation of an axonal guidance phosphoprotein collapsin
response mediator protein 2 (CRMP2) and the N-type voltage-gated calcium (CaV2.2) as well as the NaV1.7
voltage-gated sodium channel, correlates with the development of neuropathic pain through an unidentified
mechanism. In our preliminary studies, we found that interfering with the phosphorylation status of CRMP2 is
sufficient to confer protection from chronic pain. Others have found that a CRMP2 knock-in mutant mouse
where the phosphorylation site Ser522 was inactivated with alanine (crmp2S522A) had a decreased sensitivity
to pain. A mechanistic link between prevention of CRMP2 phosphorylation and effects on dysregulated
excitatory synaptic transmission underlying neuropathic pain processing has never been investigated.
Whether there is a phosphoregulatory “set-point” permitting CRMP2 to “toggle” between a presumptive non-
phosphorylated (non-pain) and phosphorylated (pain) state is not known. We find that the ratio of
pCRMP2:CRMP2 varies in human spinal cords. Based on the literature and our preliminary data, we
hypothesize that injury induced phosphorylated-CRMP2/CaV2.2 and phosphorylated-CRMP2/NaV1.7
upregulation in the sensory pathway promotes abnormal excitatory synaptic transmission in spinal cord that
leads to neuropathic pain states. In Aim 1, we will determine the molecular/cellular mechanisms underlying
aberrant excitatory synaptic transmission and neuropathic pain processing in conditions wherein CRMP2
phosphorylation is inhibited. In Aim 2, we will attempt to directly tackle NIH's Helping to End Addiction Long-
term (HEAL) initiative to speed scientific solutions to the national opioid public health crisis by: (a)
determining the side-effect profile and abuse liability of targeting CRMP2 phosphorylation with a small
molecule, and (b) determine if CRMP2 with a small molecule can be opioid sparing or decrease opioid abuse
liability. We propose to validate CRMP2 phosphorylation as a novel target in neuropathic pain using
innovative tools that include a genetic approach (crmp2S522A) mice as well as a non-opioid pharmacological
approach (a novel CRMP2-phsphorylation targeting compound). The expected results of this application are
translationally significant in that they will establish CRMP2-phosphorylation as a novel pain therapeutic
target. By demonstrating that inhibition of CRMP2 phosphorylation reverses or prevents neuropathic pain, we
will promote the discovery and validation of a novel therapeutic target (CRMP2-phosphorylation) to facilitate
the development of novel pain therapeutics – thus directly addressing the mandate...

## Key facts

- **NIH application ID:** 10615444
- **Project number:** 7R01NS120663-02
- **Recipient organization:** NEW YORK UNIVERSITY
- **Principal Investigator:** Rajesh Khanna
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $796,630
- **Award type:** 7
- **Project period:** 2020-08-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10615444

## Citation

> US National Institutes of Health, RePORTER application 10615444, Genetic and Pharmacological Validation of CRMP2 Phosphorylation as a Novel therapeutic Target for Neuropathic Pain (7R01NS120663-02). Retrieved via AI Analytics 2026-06-04 from https://api.ai-analytics.org/grant/nih/10615444. Licensed CC0.

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