# Stress-induced plasticity in noradrenergic analgesia

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2024 · $354,822

## Abstract

Project Summary
The overall goal of this research is to better understand the analgesic properties of central noradrenergic
systems. Emotional regulation in the face of physical injury and psychological trauma is critical to long-term
survival and quality of life. Uncontrollable anxiety, anhedonia, and depression often result following periods of
prolonged stress or chronic pain. Both chronic pain and stress lead to overlapping physiological adaptations
such that the same tricyclic and serotonin/norepinephrine reuptake inhibitors (SNRIs) developed and used to
treat depression are also effective in treating chronic pain. Therefore, norepinephrine (NE) is likely one of the
key neurotransmitters regulating pain processing during stress. In this proposal we seek to define the role of
NE in stress-induced modification of pain. The locus coeruleus-noradrenergic (LC-NE) system is one particular
central nervous system target that holds promise for interventions in both chronic pain and stress-induced
psychiatric disorders. This research focuses on understanding the mechanisms by which the LC-NE system
modulates endogenous analgesia and how chronic stress affects this system. The central hypothesis of this
proposal is that LC-NE neuronal activity is critical for stress-induced modulation of nociception. The first aim of
this proposal will assess the role of LC-NE neurons in acute stress-induced antinociception using in vivo
optogenetics and chemogenetics. The second aim seeks to understand the mechanism for the transition from
acute stress-induced antinociception to chronic stress-induced pronociception. In particular, this aim seeks to
determine whether repeated LC-NE stimulation from repeated stress exposure drives stress-induced
pronociception. To do so we will use, using in vivo optogenetics, chemogenetics, and intersectional genetic
models to remove LC-NE function during repeated restraint stress. The final aim seeks to clarify how two
different models for studying chronic stress reveal opposing pain-related phenotypes. Here, we will use brain
slice electrophysiology and in vivo fiber photometry to monitor LC-NE activity following these stress paradigms
and in response to noxious stimuli. Together these experiments will generate previously unattainable
information about LC-NE neurons and associated efferent circuitry that regulate the pain-related behaviors in
response to stressors. These studies will define the role of the LC-NE system; 1) in acute stress-induced
analgesia, 2) the transition to chronic stress-induced hyperalgesia, and 3) identify mechanisms by which
different forms of stress alter LC-NE function and nociception. This information will be critical for translational
research targeting the noradrenergic system in the treatment of pain and neuropsychiatric disorders.

## Key facts

- **NIH application ID:** 10884233
- **Project number:** 5R01NS117899-05
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Jordan G. McCall
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $354,822
- **Award type:** 5
- **Project period:** 2020-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10884233

## Citation

> US National Institutes of Health, RePORTER application 10884233, Stress-induced plasticity in noradrenergic analgesia (5R01NS117899-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10884233. Licensed CC0.

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