# Targeting melanocortin-4 receptors to reduce pain in U.S. Veterans

> **NIH VA I01** · SOUTHEAST LOUISIANA VETERANS HEALTH CARE · 2024 · —

## Abstract

Project Summary
Approximately 65% of Veterans report pain in the last 3 months, and >50% of Veterans receiving care at VHA
facilities report chronic pain. Chronic pain syndromes are more common among female veterans, and adults
under age 24 comprise ~10% of the U.S. military, but little is known about differences in neurobiological
mediators of chronic pain that starts in adolescence versus adulthood. The first-line treatment approach for
chronic pain over the last few decades has been opioid drugs, but this approach has created a major health
crisis defined by high rates of prescription opioid abuse, high rates of opioid use disorder in pain patients, high
rates of recreational opioid users starting with prescription opioids, and high rates of opioid-related deaths.
Here, we propose experiments that test melanocortin-4 receptors (MC4Rs) as a target for treatment of chronic
inflammatory pain. MC4Rs are widely distributed in CNS, with endogenous agonist (alpha-melanocyte-
stimulating hormone) and endogenous antagonist (agouti-related protein) ligands. MC4R and its ligands are
expressed in ascending and descending pain pathways, including in central amygdala (CeA) and
periaqueductal gray (PAG). The ventrolateral PAG (vlPAG) receives dense CeA input and feeds into
descending pain modulation circuits. Prior work by our lab and others showed that central MC4R blockade has
anti-pain effects of its own, and also that it potentiates the analgesic effects of acute morphine, blocks the
development of tolerance to the analgesic effects of chronic morphine, and blocks morphine withdrawal-
induced hyperalgesia.
Here, our overarching hypothesis is that brain MC4Rs are a promising novel non-opioid target for reducing
nociception in individuals living with chronic inflammatory pain. We will test this hypothesis in complementary
aims that use convergent techniques to 1) examine the neurobiological effects of chronic inflammatory pain
that starts during adulthood or adolescence in males and females, and 2) test the effect of intranasally
delivered MC4R antagonist on chronic inflammatory pain. Specific Aim 1 will test the prediction that chronic
inflammatory pain produces age-specific changes in nociception and pain avoidance, CeA MC4R expression
and CeA-vlPAG circuit activity in adolescent and adult male and female rats. Specific Aim 2 will test the
prediction that intra-CeA MC4R antagonism and CeA-vlPAG circuit stimulation rescue inflammatory
hyperalgesia and pain avoidance in adolescent and adult male and female rats. Specific Aim 3 will test the
predictions that intra-nasal MC4R antagonism rescues inflammatory hyperalgesia and enhances morphine
anti-hyperalgesic effects.

## Key facts

- **NIH application ID:** 10768697
- **Project number:** 5I01BX003451-07
- **Recipient organization:** SOUTHEAST LOUISIANA VETERANS HEALTH CARE
- **Principal Investigator:** Nicholas Warren Gilpin
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2017-01-01 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10768697

## Citation

> US National Institutes of Health, RePORTER application 10768697, Targeting melanocortin-4 receptors to reduce pain in U.S. Veterans (5I01BX003451-07). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10768697. Licensed CC0.

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