# Role of Stress-induced LC Dysfunction on Pain Trajectory and Disability after Surgery

> **NIH NIH P01** · WAKE FOREST UNIVERSITY HEALTH SCIENCES · 2020 · $152,534

## Abstract

The failure of pain to resolve after surgery has a significant impact on the physical function, emotional well-
being, and overall quality of life for those affected often leading to long term disability. As a result, the
identification of interventions that prevent or treat chronic pain after surgery (CPAS) has the potential to
significantly impact public health. Clinically, a person’s capacity to engage endogenous analgesic circuits as
well as a negative preoperative cognitive affective state have been shown to predict a higher incidence of pain
and disability several months after surgery. The causal mechanisms responsible for these relationships are not
understood. The central hypothesis of this research proposal is that locus coeruleus (LC) noradrenergic
projections to the spinal cord and central amygdala (CeA) are important for resolution of pain and disability
following surgery and increased tonic LC activity induced by chronic stress around the time of surgery disrupts
noradrenergic circuits and receptor mediated signaling pathways resulting in long term disability affecting
multiple behavioral domains (sensory, cognitive, affective).
 A barrier to the field is a lack of appropriate animal models and approaches to study the mechanisms that
underlie these associations. In the current project, we use novel and innovative methods to study the
interaction between LC activity, chronic stress, and recovery from pain and disability after surgery.
We apply growth curve modeling to longitudinal measures of mechanical hypersensitivity and a novel non-
evoked measure of disability involving running wheel performance to better characterize the resolution of
postoperative pain and disability in individual rats. We recently demonstrated for the first time in an animal
model that lower preoperative CPM was associated with smaller slope of recovery of hypersensitivity following
surgery and spinal noradrenergic pathways were critical to both CPM and speed of recovery. Expanding on
these findings, we demonstrate that exposing rats to repeat social defeat (RSD) stress reduces preoperative
CPM and slows recovery of hypersensitivity and reduces mobility.
 As part of Aim 1, we will examine the influence of augmenting spinal noradrenergic activity on preoperative
CPM and postoperative hypersensitivity and disability. Additionally, we will engineer and use DREADD
containing viral vectors to selectively excite/silence noradrenergic circuits at the terminal to better understand
the contribution of specific projections (to spinal cord and CeA) to aspects of recovery. As part of Aim 2, we
examine how experimentally increasing LC tonic activity with RSD impacts sensory evoked LC activity and
NE release to regulate recovery from surgery. In Aim 3, we will test whether preoperative tonic LC activity
and CPM predicts the efficacy of systemic gabapentin and duloxetine to speed recovery from hypersensitivity
and reduced mobility in individual rats. Together, this project a...

## Key facts

- **NIH application ID:** 9900813
- **Project number:** 5P01GM113852-05
- **Recipient organization:** WAKE FOREST UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Christopher Michael Peters
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $152,534
- **Award type:** 5
- **Project period:** — → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9900813

## Citation

> US National Institutes of Health, RePORTER application 9900813, Role of Stress-induced LC Dysfunction on Pain Trajectory and Disability after Surgery (5P01GM113852-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9900813. Licensed CC0.

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