# Modulation of local adenosine signaling to attenuate fracture pain

> **NIH NIH R01** · DUKE UNIVERSITY · 2024 · $79,396

## Abstract

ABSTRACT
Management of pain arising from orthopedic fractures remains a challenge as common analgesic medications
such as non-steroidal anti-inflammatory drugs (NSAIDs) and opiates either interfere with healing or possess
unwanted side effects such as dependence. Given the prevalence of pain associated with orthopedic surgeries
and bone fractures, there is an urgent need to develop therapeutic strategies that can mitigate pain while
promoting fracture healing. This motivated us to study the potential use of adenosine (ADO) as a therapeutic
agent for managing fracture pain. ADO is a naturally occurring small molecule that is released upon injury and
elicits analgesic effects in peripheral and central nerves. We and others have shown that extracellular ADO is
an effective osteoanabolic agent promoting bone formation and fracture healing. The osteoanabolic function of
ADO along with the analgesic function makes it an ideal molecule to treat fracture pain. The overarching goal of
the proposal is to assess the use of ADO for the management of pain in fracture injuries by advancing the
fundamental understanding of how ADO mitigates fracture pain and developing new clinically viable therapeutic
strategies. Towards this, Aim 1 of the proposal will develop and characterize an injectable biomaterial for local
delivery of ADO to the fracture site, and determine the dose-dependent effect on fracture healing. To determine
whether biomaterial-assisted local delivery of ADO provides analgesic effects following fracture injury, studies in
Aim 2 will perform behavioral tests for pain, tissue analyses, in vitro analyses by developing DRG-on-Chip
platforms, and RNA sequencing. Aim 3 will test the hypothesis that ADO-mediated fracture pain mitigation
involves A1 receptors (A1Rs) by using animals with conditional knockout of A1R in sensory neurons, and
elucidates its regulation of ion channels. Completion of this proposal will establish a new therapeutic molecule
for the care of fracture trauma, and potentially change how bone injuries are treated. The broad impact of our
studies using localized delivery of ADO could be extended to the management of various types of acute and
chronic pain that originate in the peripheral or central nervous system.

## Key facts

- **NIH application ID:** 11058728
- **Project number:** 3R01AR079189-04S1
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Shyni Varghese
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $79,396
- **Award type:** 3
- **Project period:** 2021-04-15 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11058728

## Citation

> US National Institutes of Health, RePORTER application 11058728, Modulation of local adenosine signaling to attenuate fracture pain (3R01AR079189-04S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11058728. Licensed CC0.

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