# Extracellular mechanism regulating synaptic function and pain plasticity

> **NIH NIH R01** · THOMAS JEFFERSON UNIVERSITY · 2022 · $511,055

## Abstract

Abstract:
As much as 20% of the population will suffer from chronic pain lasting for more than 6
months. Chronic pain and its underlying pathophysiology, can result in depression and
other debilitating neurological effects and although there are effective treatments for
acute pain chronic pain is resistant to most current treatments requiring the
development of novel therapeutics that target molecular events underlying these pain
states. Neuropathic and persistent post-surgical pain occurs, at least in part, due to long
lasting changes in the function of excitatory synaptic transmission in the spinal dorsal
horn resulting in enhanced pain signalling (hyperalgesia) and innocuous stimuli evoking
pain (allodynia). These synaptic events share many features of neuronal plasticity that
has been studied in higher CNS areas. Many of these changes are NMDAR dependent
resulting in increased synaptic strength. One mechanism that has emerged underlying
these changes in synaptic function is the potentiation of NMDAR function by a direct
molecular interaction with the EphB receptor tyrosine kinase. Building on our published
work, we will test the hypothesis that an EphB-NMDAR interaction is responsible for the
development of a chronic pain state by directing NMDARs to synapses by expressing
wild type or mutant EphB2 receptors in vitro and in mice. To test this hypothesis, we will
determine the mechanism mediating the EphB-NDMAR interaction, characterize
molecules and other tools to disrupt this interaction, and determine whether preventing
the EphB-NMDAR interaction will alleviate chronic pain. To address these questions we
will undertake three specific aims: 1. Determine the domain on the NMDAR
responsible for the EphB-NMDAR interaction. 2. Test the hypothesis that VLK
directs phosphorylation of Y504 on EphB2. 3. Determine the functional
significance of VLK in pain plasticity. Collectively these aims will create a new
knowledge that will provide a deeper understanding of the role of EphB-NMDAR
interaction in pain and enable progress toward understanding the basic mechanisms
behind chronic pain states.

## Key facts

- **NIH application ID:** 10487409
- **Project number:** 5R01NS111976-04
- **Recipient organization:** THOMAS JEFFERSON UNIVERSITY
- **Principal Investigator:** Matthew B Dalva
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $511,055
- **Award type:** 5
- **Project period:** 2019-09-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10487409

## Citation

> US National Institutes of Health, RePORTER application 10487409, Extracellular mechanism regulating synaptic function and pain plasticity (5R01NS111976-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10487409. Licensed CC0.

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