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

> **NIH NIH R01** · UNIVERSITY OF ARIZONA · 2020 · $395,680

## Abstract

SUMMARY (Revisions in blue font)
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...

## Key facts

- **NIH application ID:** 9966187
- **Project number:** 1R01NS120663-01A1
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** Rajesh Khanna
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $395,680
- **Award type:** 1
- **Project period:** 2020-08-01 → 2022-01-05

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9966187

## Citation

> US National Institutes of Health, RePORTER application 9966187, Genetic and Pharmacological Validation of CRMP2 Phosphorylation as a Novel therapeutic Target for Neuropathic Pain (1R01NS120663-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9966187. Licensed CC0.

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