# Spinal Mechanisms Underlying SCI-Induced Pain:  Implications for Targeted Therapy

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2020 · $552,765

## Abstract

Project Summary
Spinal cord injury (SCI) causes not only in sensorimotor deficits, but also in a chronic, severe and often
unrelenting pain (SCI-pain) that occurs in as many as 85% of patients. SCI-pain has neuropathic features and
is often resistant to conventional pain therapy. The latter may reflect, in part, an incomplete understanding of
injury mechanisms. Identifying mechanisms responsible for post-injury neuropathic pain could provide targets
for more effective therapeutic interventions. We identified a promising new therapeutic target trkB.T1, a
truncated isoform of the brain-derived neurotrophic factor receptor—tropomyosin related kinase B (trkB). In
mouse models of neuropathic pain including SCI, genetic deletion of trkB.T1 reduces both mechanical and
thermal hypersensitivity. However, the precise cellular mechanisms underlying this finding are not fully
understood. The purpose of this study is to investigate how trkB.T1 drives post-injury neuropathic pain via
astrocyte dysfunction and test the hypothesis that astrocytic trkB.T1 functions as a key mechanism in post-
injury reactive astrogliosis, through altered transcriptional programming that controls cellular movement and
immune function, thus affecting chronic pain after spinal cord injury.
We will use astrocytic trkB.T1 knock out (KO), Nox2 KO, and trkB.T1-KFG knock in transgenic mice and in vivo
and in vitro innovatively technologies to determine the mechanisms of SCI-triggered trkB.T1 elevation on post-
injury hyperpathia. Aim 1 will determine the function and mechanisms of the trkB.T1/[Ca2+]i/Nox2
pathway in astrocytes after SCI. Multiple quantitative assessments of astrogliosis will be combined with a
genetic intervention targeting trkB.T1 to test the hypothesis that SCI-triggered trkB.T1 elevation in astrocytes
increases [Ca2+]i and Nox2 activity, contributing to neuroinflammation and hyperpathia. Aim 2 will elucidate
the role of astrocytic Nox2 signaling in post-injury hyperpathia. We will utilize genetic intervention to
delete trkB.T1-dependent up-regulation of Nox2 in astrocytes, and evaluate the effects on astrocytic Nox2 on
neuropathic pain after SCI. Aim 3 will determine the role for the KFG domain on trkB.T1 in the regulation
of astrocyte function and SCI-Pain. Complimentary cellular, molecular, and genetic approaches will be used
to test the hypothesis that KFG domain of trkB.T1 regulates trkB.T1 function in response to BDNF, and
mutation of KFG domain abolishes post-injury neuropathic pain.
Our study will be the first to implicate astrocytic trkB.T1-mediated [Ca2+]i/Nox2 signaling in the pathophysiology
of SCI. Our data should establish that second messenger binding to the intracellular KFG domain on trkB.T1 is
a physiologically important mechanism that regulates trkB.T1-mediated pain signaling. These observations
may lead to novel therapeutic targets for neuropathic pain in a wide range of disease states.

## Key facts

- **NIH application ID:** 9970270
- **Project number:** 5R01NR013601-09
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** SUSAN G DORSEY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $552,765
- **Award type:** 5
- **Project period:** 2012-03-21 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9970270

## Citation

> US National Institutes of Health, RePORTER application 9970270, Spinal Mechanisms Underlying SCI-Induced Pain:  Implications for Targeted Therapy (5R01NR013601-09). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9970270. Licensed CC0.

---

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