# Resolving functional pain by complementary approaches

> **NIH NIH P01** · DUKE UNIVERSITY · 2020 · $264,402

## Abstract

ABSTRACT
Functional pain syndromes (FPS) 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
reduced 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 enhanced pain following repeated stress. In
subsequent studies, we demonstrated that COMT-dependent pain is initiated by peripheral β-adrenergic
receptors through the release of pro-inflammatory cytokines (e.g., TNFα and IL-6) in plasma, and maintained
by neuroplastic changes in the central nervous system, characterized by increased expression of TNFα and
increased activation of glia and nociceptors in the spinal cord. Together, these findings suggest that heightened
adrenergic tone promotes pain, inflammation, and neuroinflammation in patients with FPS. Acupuncture and
the fish oil derivative DHA are recommended treatments for FPS, however their mechanistic effects on
inflammation and neuroinflammation associated with deficiencies in COMT have remained unstudied. We
hypothesize that acupuncture, DHA, and the DHA-derived resolvin D1 (RvD1) each produce beneficial effects
in preventing and treating functional pain exacerbated by stress via modulating immune response and
nociceptor activity. Preliminary data reveal that ST36 acupuncture reverses COMT-dependent pain and
corresponding activation of glial cells in the spinal cord. Additional data reveal that DHA reverses COMT-
dependent pain and nociceptor activity exacerbated by stress. The proposed studies will extend this work to 1)
determine the time course for the development, maintenance, and resolution of functional pain (e.g.,
mechanical allodynia and locomotor activity), inflammation (e.g., cytokines and activated macrophages and T
cells in plasma), and neuroinflammation (e.g., cytokines in CSF and activated glia in spinal cord) caused by
low COMT activity and exacerbated by stress, 2) test the effects of electroacupuncture, DHA, and RvD1 in
preventing and reversing functional pain, inflammation, and neuroinflammation in the absence or presence of
stress, and 3) test the effects of electroacupuncture (versus manual acupuncture), DHA, and RvD1 in reversing
increased activity of mechanosensitive and thermosensitive nociceptors that drive functional pain in the
absence and presence of stress. Results from these studies will advance our knowledge about the
consequences of heightened catecho...

## Key facts

- **NIH application ID:** 9703534
- **Project number:** 1P01AT009968-01A1
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Andrea G Nackley
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $264,402
- **Award type:** 1
- **Project period:** 2020-04-20 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9703534

## Citation

> US National Institutes of Health, RePORTER application 9703534, Resolving functional pain by complementary approaches (1P01AT009968-01A1). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/9703534. Licensed CC0.

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