# Age-related decline in endogenous pain modulation and its impact on osteoarthritis pain

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2024 · $509,641

## Abstract

Abstract and Project Summary
A growing number of studies show strong evidence that one mechanism predisposing older adults to an
increased risk of chronic pain conditions is an age-related decline in conditioned pain modulation (CPM), a
psychophysical index of endogenous pain inhibition. However, the central mechanisms underlying age
differences in CPM and the causal links between dysfunctional CPM and chronic pain conditions are largely
unknown. This project explores the brain networks that underlie age differences in descending noxious inhibitory
control (DNIC), a measure that is similar to CPM in preclinical settings, and the mechanistic links between
dysfunctional DNIC and osteoarthritis (OA)-related pain, a chronic pain condition that disproportionately affects
the aged population. Our prior work has demonstrated that the efficiency of DNIC is reduced in young female
rats, and DNIC efficiency is also impaired in old rats of both sexes. Additionally, we demonstrated that OA-related
primary mechanical hyperalgesia was longer-lasting and more pronounced in older rats, with aged female rats
experiencing the most severe aging effects. We then provided compelling evidence that the altered DNIC in
young female rats and old rats is strongly associated with a weaker resting functional connectivity (FC) between
the rostral anterior cingulate cortex (rACC) and the periaqueductal gray (PAG). Our studies collectively suggest
that strong rACC to PAG FC is a cornerstone of efficient DNIC, and age-related alteration in rACC to PAG FC
leads to dysfunctional DNIC and chronic OA pain. Here we propose that enhancement of the rACC to PAG circuit
in aged rats will lead to improved DNIC and that strengthening DNIC in aged rats will effectively attenuate chronic
OA pain responses. We will investigate our proposal with three specific aims (SAs). (SA1) We hypothesize that
selective activation of rACC neurons projecting to PAG will significantly enhance DNIC efficiency in aged rats.
We will use a behavioral paradigm for DNIC paired with chemogenetics to experimentally manipulate the strength
of the rACC to PAG circuit in aged male and female rats. (SA2) We will investigate the potential causal
relationship between DNIC and OA responses in aged rats. We hypothesize that scaling up DNIC efficiency by
enhancing the rACC to PAG circuit significantly improves OA outcomes in aged rats. We will conduct a
concurrent fMRI study to confirm that experimental manipulation of DNIC circuitry restores OA-induced changes
in the brain networks of aged male and female rats. (SA3) Exercise is known to enhance CPM in humans. Our
preliminary data show that regular exercise can also significantly improve DNIC in aged rats. We hypothesize
that exercise increases the strength of the rACC to PAG circuit, thereby enhancing DNIC, reducing OA-related
pain, and restoring altered brain networks in aged male and female rats. These studies will significantly improve
our knowledge regarding the impac...

## Key facts

- **NIH application ID:** 10817049
- **Project number:** 5R01AG073136-03
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** JIN Y Ro
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $509,641
- **Award type:** 5
- **Project period:** 2022-06-01 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10817049

## Citation

> US National Institutes of Health, RePORTER application 10817049, Age-related decline in endogenous pain modulation and its impact on osteoarthritis pain (5R01AG073136-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10817049. Licensed CC0.

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