# Experimental model of chronic pain risk: Insomnia, inflammation, central sensitization, and affective disturbance

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2021 · $663,838

## Abstract

PROJECT SUMMARY
Chronic pain and depressive disorders differentially impact older adults and both conditions are often intractable,
underscoring the need to investigate modifiable risk factors and better elucidate the pathophysiology of these
disorders. Insomnia, a cardinal symptom of both disorders, is modifiable, yet it is not known how insomnia
influences biological and central nervous system factors that increase risk for chronic pain. This knowledge is
critical for refining insomnia and chronic pain management therapies to target alterations in central pain
processing that contribute to chronic pain risk and morbidity. Given that insomnia and sleep disturbance activate
inflammatory signaling, the proposed study hypothesizes that inflammation is a common biological substrate that
dynamically links insomnia and affective disturbance with alterations in two dimensions of central pain processing
associated with chronic pain risk, i.e. central sensitization (CS) and affective pain modulation (APM). Animal
models demonstrate that inflammation heightens pain sensitivity and induces neuroplastic alterations that
increase the responsivity of CNS nociceptive neurons to normal or subthreshold afferent input, i.e., CS.
Inflammation also induces affective disturbances that may modulate and amplify pain perception (APM). Low
dose endotoxin administration safely and transiently induces affective disturbance and emerging studies suggest
this inflammatory challenge may alter CS. Hence, we will investigate whether insomnia, alone or combined with
an experimental inflammatory challenge (endotoxin) alters CS and APM in older adults. This proposal synergizes
with a newly funded study [(R01 AG051944 (Irwin)] of differences in depressive symptoms and negative and
positive affect responding as a function of insomnia and inflammatory challenge. We will study a subset (N=148)
of participants in this parent study of older adults with (N=74) and without (N=74) insomnia who will complete a
comprehensive assessment of pain processing (CS and APM) following exposure to endotoxin vs. placebo. To
further establish the translational promise of this experimental model of chronic pain risk, we will add electronic
diary assessments of daily pain and depressive symptoms at 3, 6, 9, and 12 months. We will address four aims:
1) Evaluate differences in indices of central sensitization (CS) as a function of insomnia and experimental
endotoxin exposure; 2) Evaluate differences in affective pain modulation (APM) as a function of insomnia and
experimental endotoxin exposure and determine the extent to which endotoxin-induced affective disturbance
accounts for alterations in CS and APM; 3) Determine whether individual differences in the endotoxin-induced
inflammatory response are associated with alterations in CS and APM, as a function of insomnia and 4)
Determine the extent to which the endotoxin-induced inflammatory response and/or alterations in CS, APM, and
affective disturbance pre...

## Key facts

- **NIH application ID:** 10145565
- **Project number:** 5R01AG057750-04
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Michael T Smith
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $663,838
- **Award type:** 5
- **Project period:** 2018-08-15 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10145565

## Citation

> US National Institutes of Health, RePORTER application 10145565, Experimental model of chronic pain risk: Insomnia, inflammation, central sensitization, and affective disturbance (5R01AG057750-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10145565. Licensed CC0.

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