# Defining the role of peripheral Adrb3 in chronic pain and inflammation

> **NIH NIH R01** · DUKE UNIVERSITY · 2020 · $524,671

## Abstract

ABSTRACT
Functional pain syndromes affect over 100 million people, yet remain ineffectively treated because the causes
are largely unknown. Accumulating evidence suggests that these syndromes are due, in large part, to low
activity of catechol-O-methyltransferase (COMT), an enzyme that metabolizes catecholamines. An estimated
66% of patients with functional pain syndromes, such as fibromyalgia, possess variants in the COMT gene that
lead to low activity of the COMT enzyme. Individuals with the ‘low COMT activity’ genotype report greater pain
at baseline and enhanced pain following stressful events that potentiate catecholamine release from
sympathetic nerves. Consistent with clinical syndromes, our lab has shown that pharmacologic inhibition of
COMT in rodents produces pain at multiple body sites and enhances pain following repeated stress. In
subsequent studies, we demonstrated that COMT-dependent pain is initiated by peripheral adrenergic receptor
beta-3 (Adrb3) through the release of pro-inflammatory cytokines in local tissues. The pain is maintained by
subsequent increases in pro-inflammatory cytokines in spinal tissues and activation of mitogen activated
protein kinases (MAPKs) in the cell bodies and central terminals of pain-sensing nociceptors. Together, these
data show that heightened catecholamine tone leads to chronic pain via peripheral Adrb3 and its downstream
effectors. However, the cell types that express Adrb3 and mediate pain still need to be identified and the
molecular mechanisms determined. We hypothesize that activation of Adrb3 on adipocytes (fat cells that
surround peripheral nociceptor and sympathetic nerve terminals) drives chronic COMT-dependent pain via
increases in cytokines and MAPKs that promote inflammation and nociceptor activation. Further, we
hypothesize that stress-induced catecholamine release amplifies the effects of Adrb3 signaling on inflammation
and pain. Preliminary data reveal that COMT-dependent increases in pro-inflammatory cytokines are mediated
by Adrb3 located on adipocytes. Additional data reveal that sustained activation of Adrb3 leads to decreased
levels of miR-133a, a microRNA expressed in adipocytes that is able to block MAPK signaling. The proposed
studies will extend this work to directly determine 1) Adrb3 and miR-133a expression patterns in adipose vs
other peripheral tissues over time and their relationship to COMT-dependent functional pain, 2) the role of
peripheral Adrb3 and miR-133a in mediating COMT-dependent inflammation and neuroinflammation, 3) the
role of peripheral Adrb3 and miR-133a in mediating COMT-dependent increases in the activity of
mechosensitive and thermosensitive nociceptors, and 4) how these molecular and behavioral phenotypes are
influenced by stress. Results from these studies will advance our knowledge about the mechanisms whereby
peripheral Adrb3 drives chronic pain and elucidate new targets for the development of peripherally-restricted
therapies with improved speci...

## Key facts

- **NIH application ID:** 10009478
- **Project number:** 5R01NS109541-02
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Andrea G Nackley
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $524,671
- **Award type:** 5
- **Project period:** 2019-09-15 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10009478

## Citation

> US National Institutes of Health, RePORTER application 10009478, Defining the role of peripheral Adrb3 in chronic pain and inflammation (5R01NS109541-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10009478. Licensed CC0.

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