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

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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.