# Mechanisms of Central Sensitization

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2021 · $511,374

## Abstract

Abstract
Chronic pain represents an immense clinical problem, with over 100 million Americans afflicted and an
annual price tag exceeding half a trillion dollars, according to a recent report from the Institute of Medicine.
Studies in our lab are designed to identify molecular, cellular, and circuit mechanisms of sensitization in
pain pathways with the goal of identifying novel targets for analgesic intervention. Studies performed in
our lab previously identified a critical signaling cascade in neurons of the central nucleus of the amygdala
(CeA) that underlies central pain sensitization. This pathway is initiated by metabotropic glutamate
receptor subtype 5 (mGlu5) activation of extracellular signal-regulated kinase/ERK signaling, leading to
increased firing of CeA neurons. This increase in excitability likely contributes to central sensitization
associated with persistent pain. Our prior work, and that of several other groups, suggests that neurons
in the CeA represent a critical node of neuromodulation underlying the development of chronic pain. An
important finding from our prior studies was that this maladaptive plasticity in the CeA leading to
persistent pain sensitization is specific to the right hemisphere. That is, no matter the sight of the injury,
plasticity in the right (and not left) CeA was responsible for bilateral pain hypersensitivity. Furthermore,
manipulation of neural activity only in the right CeA was found to produce bilateral pain sensitization. The
mechanisms generating this hemispheric lateralization are completely unknown. In the present
application, we will conduct a series of studies aimed at understanding the circuit context of CeA neurons that
are activated by acute pain sensitization. We will perform studies aimed at identifying critical inputs, the type
of plasticity that occurs at these synapses, and the major outputs of pain-responsive CeA neurons. We will
test whether CeA neurons activated in the context of pain sensitization are necessary and sufficient for the
development of pain sensitization, ongoing pain and comorbid disorders. By specifically targeting pain-
activated neurons in this study, we may be able to determine if they possess unique neurochemical
properties that represent novel therapeutic targets, or genetic signatures that would enable future studies to
more precisely determine their function. In vivo 2-photon imaging and microendoscope cameras will be
used to monitor activity of these neurons using genetically-encoded Ca2+ sensors, over days to weeks, to
determine how the properties of these neurons change during the transition from acute to persistent pain. We
will ask whether the population of neurons responsive to heat, cold, or touch change over time, and whether
altered activity of these neurons in persistent pain conditions can be normalized using treatments that reduce
pain or comorbid anxiety. These studies employ a host of modern techniques including advanced viral
tracing, genetic mapp...

## Key facts

- **NIH application ID:** 10188656
- **Project number:** 5R01NS106953-04
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Robert W Gereau
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $511,374
- **Award type:** 5
- **Project period:** 2018-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10188656

## Citation

> US National Institutes of Health, RePORTER application 10188656, Mechanisms of Central Sensitization (5R01NS106953-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10188656. Licensed CC0.

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