# Chronic Stress Induces Neuroimmune Modulated Primary Muscle Afferent Sensitization

> **NIH NIH R21** · UNIVERSITY OF NEW ENGLAND · 2022 · $390,500

## Abstract

SUMMARY
Many patients with chronic pain concomitantly present with increased levels of stress and anxiety. Multiple
reports point to the immune system as a potential link between stress and chronic pain development. Stress
activates immune cells and increases pro-inflammatory cytokines, which can modulate peripheral sensitization
and regulate prolonged hypersensitivity through gene expression changes in primary sensory neurons. Our
objective is to characterize the stress-induced neuroimmune interactions that modulate primary afferent
sensitization and lead to the development of prolonged ischemic muscle pain. Macrophages are one of the key
immune cells involved in these neuroimmune interactions that regulate peripheral sensitization, but the role of
macrophages in development of stress-induced muscle hyperalgesia and hypersensitivity remains unknown.
This proposal explores effects of stress in the peripheral nervous system in a new way -- selectively inhibiting
or enhancing macrophage -mediated inflammatory responses to stress and testing its role in the development
muscle pain-related behaviors. It will use and validate a never before used, loss of environmental enrichment
(LOE) mouse model of stress that does not employ the potential confounder of noxious physical stimulation.
Interestingly, this paradigm replicates a stressor frequently experienced during the COVID-19 pandemic - LOE
due to social distancing. Our preliminary data showed gene expression changes in the dorsal root ganglia
(DRG) and innervated tissue modulated response properties of muscle afferents after ischemic injury (I/R)
modulated, in part, by proinflammatory cytokine signaling. LOE induced stress resulted in increased pain-
related behaviors after injury and increased macrophage infiltration in skeletal muscle. We hypothesize that
LOE-induced stress induces peripheral sensitization via immune cell-dependent mechanisms to
modulate the development of ischemic myalgia. We will use transgenic and chemogenetic approaches in
mice with LOE-related stress plus ischemic/reperfusion (I/R) injury, our ex vivo hind paw muscle afferent
recording strategies and pain-related behavioral assays. Aim 1 will identify if stress modulates peripheral
sensitization after injury (I/R) through macrophage infiltration by depleting macrophages in macrophage fas-
induced apoptosis (MaFIA) mice exposed to LOE with or without I/R. Electrophysiological experiments will be
paired with detailed profiling of the transcriptome of the DRG under stress. Aim 2 will evaluate the role of stress-
induced immune alterations in peripheral sensitization after I/R by using transgenic mice expressing designer
receptors exclusively activated by designer drugs (DREADDs) driven by Cre-recombinase expression from the
Lysozyme-2 promotor (LysM, only expressed myelomonocytic cells, such as macrophages).Characterization of
the mechanisms of stress-induced neuroimmune interactions that modulate primary afferent sensitization w...

## Key facts

- **NIH application ID:** 10754766
- **Project number:** 7R21NS125484-02
- **Recipient organization:** UNIVERSITY OF NEW ENGLAND
- **Principal Investigator:** Luis Fernando Queme Cobar
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $390,500
- **Award type:** 7
- **Project period:** 2022-12-15 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10754766

## Citation

> US National Institutes of Health, RePORTER application 10754766, Chronic Stress Induces Neuroimmune Modulated Primary Muscle Afferent Sensitization (7R21NS125484-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10754766. Licensed CC0.

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