# Molecular Determinants of Synaptic Plasticity in Chronic Pain

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2021 · $427,286

## Abstract

Project Summary
The overall goal of our research program is to elucidate the underlying molecular principles that govern synaptic
plasticity associated with chronic pain. Chronic neuropathic pain is a significant and unmet clinical problem.
Glutamate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) mediate the vast majority
of fast excitatory synaptic transmission in the mammalian central nervous system. AMPARs are tetrameric cation
channels composed of a combinational assembly of four subunits, GluA1 through GluA4. GluA2 is particularly
important for the biophysical properties of AMPARs because GluA2-containing AMPARs are impermeable to Ca2+.
In contrast, GluA2-lacking AMPARs show inward-rectifying currents and have a high Ca2+ permeability and are
thus referred to as Ca2+-permeable AMPARs (CP-AMPARs). The prevalence of synaptic CP-AMPARs of spinal
dorsal horn neurons is markedly increased in neuropathic pain. However, the molecular mechanisms underlying
the switch of AMPAR subunit composition in neuropathic pain remain little known. The major objective of our
proposal is to determine the key molecular mechanism responsible for regulating the assembly and trafficking of
CP-AMPARs in neuropathic pain. α2δ-1, often considered a Ca2+ channel subunit, is upregulated in the spinal
dorsal horn in neuropathic pain. Our preliminary studies showed that α2δ-1 interacted with AMPAR subunits in vitro
and in vivo and that increased α2δ-1 expression promoted synaptic incorporation of CP-AMPARs in the spinal
dorsal horn. In this proposal, we will test our overall hypothesis that α2δ-1 potentiates the synaptic CP-AMPAR
prevalence in spinal dorsal horn neurons in neuropathic pain through physical interaction with AMPAR subunits
to preferentially regulate their subunit composition and synaptic trafficking. We will use a multidisciplinary approach
to study α2δ-1–AMPAR coupling and its distinct role in neuropathic pain at molecular, cellular, and behavioral
levels. At the completion of our project, we will gain significant mechanistic insight into the poorly defined role of
α2δ-1 in synaptic plasticity and neuropathic pain caused by nerve injury and diabetic neuropathy. This new
information will redefine the physiological function α2δ-1 and the role of α2δ-1–bound CP-AMPARs in the
therapeutic effects of gabapentinoids. Therefore, the findings from the proposed studies will have a sustained
positive impact by advancing our understanding of the synaptic mechanism of neuropathic pain, leading to the
development of new therapies for chronic neuropathic pain.

## Key facts

- **NIH application ID:** 10202744
- **Project number:** 5R01NS101880-05
- **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:** 2021
- **Award amount:** $427,286
- **Award type:** 5
- **Project period:** 2017-08-15 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10202744

## Citation

> US National Institutes of Health, RePORTER application 10202744, Molecular Determinants of Synaptic Plasticity in Chronic Pain (5R01NS101880-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10202744. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*