# Molecular Determinants of Synaptic Plasticity in Chronic Pain

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2024 · $486,998

## Abstract

Molecular Determinants of Synaptic Plasticity in Chronic Pain
The long-term goal of our project is to identify the molecular and signaling mechanisms that govern synaptic
plasticity under chronic pain conditions. Neuropathic pain remains a major therapeutic challenge, and neuronal
plasticity at the spinal cord level is fundamentally important to the development of chronic neuropathic pain. N-
methyl-D-aspartate receptors (NMDARs) are expressed in primary sensory neurons and their central terminals
in the spinal dorsal horn. However, they are functionally inactive under normal conditions and become tonically
activated to potentiate glutamatergic input to spinal dorsal horn neurons after nerve injury and chemotherapy-
induced neuropathy. The molecular mechanisms regulating the synaptic activity and trafficking of NMDARs in
the spinal dorsal horn remain poorly understood. Volume-regulated anion channels, which are formed by multiple
different leucine-rich repeat-containing protein 8 (LRRC8) family members, are crucial to the regulation of cell
volume. In our pilot studies, we found that LRRC8A was highly expressed in dorsal root ganglion (DRG) neurons.
Also, traumatic nerve injury selectively downregulated LRRC8A, but not LRRC8B-LRRC8D, in the DRG.
Furthermore, LRRC8A downregulation or conditional knockout in DRG neurons induces NMDAR-dependent
pain hypersensitivity. Importantly, we discovered that LRRC8A physically interacted with NMDARs to control
synaptic trafficking and activity of NMDARs. In this renewal application, we will specifically determine the roles
of LRRC8A in the regulation of nociception and synaptic NMDARs at the spinal cord level in two neuropathic
pain models. On the basis of our intriguing preliminary data, we propose to test the overall hypothesis that
LRRC8A protein directly interacts with NMDARs and normally restrains the synaptic trafficking of NMDARs at
the spinal cord level; nerve injury or chemotherapy diminishes LRRC8A expression and augments the synaptic
expression and activity of NMDARs, leading to increased glutamatergic input to spinal dorsal horn neurons and
chronic pain. We will apply several innovative and complementary approaches, including biochemical and
cellular analyses, transgenic mice, and synaptic recordings to study how LRRC8A controls NMDARs and
nociception at molecular, cellular, and behavioral levels. Our project will generate fundamental new information
about the molecular basis of NMDAR-mediated synaptic plasticity in neuropathic pain. Findings from our project
are expected to advance our knowledge of molecular mechanisms of nociceptive regulation and to guide the
development of new strategies for treating chronic neuropathic pain.

## Key facts

- **NIH application ID:** 10746841
- **Project number:** 5R01NS101880-07
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Shao-Rui Chen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $486,998
- **Award type:** 5
- **Project period:** 2017-08-15 → 2027-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10746841

## Citation

> US National Institutes of Health, RePORTER application 10746841, Molecular Determinants of Synaptic Plasticity in Chronic Pain (5R01NS101880-07). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10746841. Licensed CC0.

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