Turn the switch “off” on pain.
Opioids are often used to treat chronic pain, though they come with several risks. Scientists are using artificial intelligence to identify pain-processing areas in the brain, then applying gene therapy to modify those areas and treat pain without relying on opioid medications.
“Trapped in a body that yields endless pain.
There is no escape, and it makes me insane.
The pain changes daily, but it is always there.
There’s no end in sight, and I’m nearing despair.”
– Jennifer MacDonald
This poem emphasizes the struggle for people who live with chronic pain. Nearly one in four adults in the U.S. lives with chronic pain (1). Chronic pain is a silent epidemic, impacting more than 50 million Americans, costing our society an estimated 565 to 635 billion dollars annually in direct medical expenses and indirect costs from lost productivity, including missed work and reduced earning capacity (2). This pain is invisible to everyone but the person living with it. The gap exists because we still don’t fully understand the neurological processes that perpetuate pain after injury or disease, and what can’t be seen by everyone is often undertreated.
Opioids work by binding to specific opioid receptors (mu, delta, kappa) in the brain, spinal cord, and gut, mimicking natural chemicals, called endorphins, in the body to block pain signals. They act on the limbic system, which controls emotions and creates feelings of pleasure, the brainstem, which controls breathing, and the spinal cord, which receives pain signals from the body and sends them to the brain. Dealing with chronic pain can feel like listening to a radio where the volume is stuck at maximum volume, and the noise never seems to lessen. The first-ever gene therapy has the potential to turn down the volume on the pain signal without affecting the rest of the brain. This preclinical study, published in January 2026 in the journal Nature, was conducted by scientists from the University of Pennsylvania Perelman School of Medicine and School of Nursing, along with collaborators from Carnegie Mellon University and Stanford University. “The goal was to reduce pain while lessening or eliminating the risk of addiction and dangerous side effects,” said Gregory Corder, co-senior author of the study (3).
Morphine is a drug derived from opium and is widely used to treat chronic pain, but it carries a high potential for dependence, misuse, and tolerance. Tolerance means patients need increasingly higher doses to achieve the same level of pain relief. Morphine also has potential side effects like constipation, drowsiness, and, in higher doses, respiratory depression or even death. To find a safer alternative, researchers studied the brain cells responsible for tracking pain signals. The anterior cingulate cortex, or ACC, is a key region in the brain that controls the affective and motivational dimensions of pain. It controls how much pain bothers someone, not just how much one physically feels it. Targeting neurons in this area can reduce emotional and motivational aspects of pain. Scientists used an AI-powered, deep learning behavioral analysis, called Light Automated Pain Evaluator (LUPE), to assess pain states in freely moving mice. It is named after the Greek daemon of pain and suffering (Lýpē; λῡ́πη). LUPE automates the analysis of natural pain behaviors, such as paw-directed licking or guarding, using video tracking to replace subjective, manual human scoring in mice. Not only does it estimate pain levels, but it also helps determine how much treatment is needed. This system helped researchers design a biologically inspired gene therapy that targets the same neurons in the ACC that morphine acts on, using a synthetic μ-opioid receptor promoter to quiet those cells down. The result is a treatment that reproduces morphine’s pain-relieving effects in a precise and safe fashion, without risk of addiction (4).
The urgency of safer pain treatments has never been greater. The chronic pain epidemic and opioid misuse continue to rise. In 2019 alone, drug use was linked to 600,000 deaths worldwide, with 80 percent involving opioids (5). Building on this research, the team is now collaborating with Michael Platt, PhD, James S. Riepe University Professor, to move the work towards a clinical trial. As Dr. Platt says, “The journey from discovery to implementation is long, and this represents a strong first step. The potential to relieve suffering without fueling the opioid crisis is exciting.”
Works cited:
- Lucas, J. W., & Sohi, I. (2024). Chronic pain and high-impact chronic pain in US adults, 2023.
- Katzman, J. G., & Gallagher, R. M. (2024). Pain: the silent public health epidemic. Journal of Primary Care & Community Health, 15, 21501319241253547.
- https://www.sciencedaily.com/releases/2026/03/260328043558.htm
- Oswell, C. S., Rogers, S. A., James, J. G., McCall, N. M., Hsu, A. I., Salimando, G. J., … & Corder, G. (2026). Mimicking opioid analgesia in cortical pain circuits. Nature, 1-10.
- https://www.who.int/news-room/fact-sheets/detail/opioid-overdose
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