# Sleep fragmentation by brief awakenings as a surrogate to measure neuropathic spontaneous pain

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2021 · $384,813

## Abstract

Project Summary/Abstract
Most preclinical research on neuropathic pain has focused almost exclusively on mechanical allodynia and
thermal hyperalgesia as endpoint readouts. While these are pertinent to assess stimulus-evoked
hypersensitivity, they leave out the two top complaints reported by neuropathic pain patients: spontaneous pain
and sleep disturbances. There is currently no technique to measure spontaneous pain reliably in rodents,
limiting our study of the mechanisms responsible, and the nature of the sleep disturbances in neuropathic pain
states are not known.
We analyzed sleep and pain responses in two mouse models of peripheral neuropathic pain and found that
while peripheral nerve trauma did not change total sleep amount, it caused a severe non-rapid eye movement
sleep (NREMS) fragmentation in both models, which was only detected when mice also displayed signs of
abnormal pain hypersensitivity and resolved when evoked pain sensitivity returned to pre-injury values. The
temporal profile of the wake episodes that fragment sleep fits with the very brief sharp pain burst reported in
patients with traumatic neuropathic pain (1), and also with the rare occurrence of spontaneous pain-like
behavior observed in awake rodents after trigeminal nerve injury (2-4).
In our pilot data, we used a combination of genetic and pharmacological approaches and found that the
increase in sleep fragmentation after nerve injury originates from injured peripheral sensory neurons, does not
appear to be caused by peripheral inputs and can be blocked by analgesics. In this project we hypothesize that
sleep fragmentation caused by nerve injury is causally linked to the spontaneous activity in sensory
fibers that activates pain pathways, and that therefore it could be used as a surrogate readout for
quantifying neuropathic spontaneous pain.
We propose 3 Specific Aims to test if sleep fragmentation after nerve injury is caused by ectopic activation of
injured sensory neurons that activates ascending pain pathways, while it does not involve innocuous stimuli or
require evoked noxious stimuli.
Aim 1: Identify which peripheral sensory neurons drive NREMS fragmentation after nerve injury.
Aim 2: Determine if the neural activity responsible for NREMS fragmentation is generated spontaneously at
the injury site or requires external stimuli.
Aim 3: Test if the spino-parabrachial pathway contributes to nerve injury-induced NREMS fragmentation
Because we cannot measure spontaneous pain in live animals it has been impossible to perform mechanistic
studies. Identifying a novel readout measure for neuropathic spontaneous pain would represent a fundamental
breakthrough to study the underlying mechanisms and test the efficacy of potential novel analgesics.

## Key facts

- **NIH application ID:** 10131279
- **Project number:** 5R01NS112266-02
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Alban A Latremoliere
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $384,813
- **Award type:** 5
- **Project period:** 2020-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10131279

## Citation

> US National Institutes of Health, RePORTER application 10131279, Sleep fragmentation by brief awakenings as a surrogate to measure neuropathic spontaneous pain (5R01NS112266-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10131279. Licensed CC0.

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