Living with chronic pain is often compared to having a radio stuck at full volume, where the noise never fades no matter what you try. Opioids such as morphine can lower that volume, but they also act on other parts of the brain, which can lead to serious side effects and a high risk of addiction.

Researchers say this new gene therapy works more like a precise volume control that turns down only the pain signal while leaving the rest of the brain unaffected. The work, published in 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, PhD, co-senior author and assistant professor of Psychiatry and Neuroscience at Penn. “By targeting the precise brain circuits that morphine acts on, we believe this is a first step in offering new relief for people whose lives are upended by chronic pain.”

AI Helps Map Pain Circuits for Safer Treatments

Morphine, a drug derived from opium, is widely used for pain relief but carries a high potential for misuse. Over time, patients often develop tolerance, meaning they need increasingly higher doses to achieve the same level of relief.

To better understand how morphine works, researchers studied brain cells involved in tracking pain signals. Using these insights, they built an artificial intelligence (AI)-powered system in mice that monitors natural behavior, estimates pain levels, and helps determine how much treatment is needed.

This system served as a guide for designing a targeted gene therapy that reproduces morphine’s pain-relieving benefits without triggering addiction. The therapy introduces a brain-specific “off switch” for pain. When activated, it reduces pain over a sustained period without interfering with normal sensations or activating reward pathways associated with addiction.

“To our knowledge, this represents the world’s first CNS-targeted gene therapy for pain, and a concrete blueprint for non-addictive, circuit-specific pain medicine,” Corder said.

Addressing Chronic Pain Without Fueling the Opioid Crisis

The research reflects more than six years of work supported by a National Institutes of Health New Innovator Award, which enabled the team to investigate how chronic pain develops and persists.

The urgency of safer treatments is clear. In 2019, drug use was linked to 600,000 deaths, with 80 percent involving opioids. A 2025 Pew survey found that nearly half of Philadelphians knew someone with opioid use disorder (OUD), and one-third knew someone who had died from an overdose.

At the same time, chronic pain remains a widespread and costly condition, often described as a ‘silent epidemic.’ It affects about 50 million Americans and leads to more than $635 million in annual costs, including medical expenses and lost productivity from missed work and reduced earnings. If future studies confirm these findings, this new approach could help reduce that burden by offering effective pain relief without the risks tied to opioids.

Next Steps Toward Clinical Trials

The research team is now collaborating with Michael Platt, PhD, the James S. Riepe University Professor, Professor of Neuroscience, Professor of Psychology, to advance the work toward potential clinical trials.

“The journey from discovery to implementation is long, and this represents a strong first step,” Platt said. “Speaking both as a scientist and as a family member of people affected by chronic pain, the potential to relieve suffering without fueling the opioid crisis is exciting.”

This work was supported by the National Institutes of Health (NIGMS DP2GM140923, NIDA R00DA043609, NIDA R01DA054374, NINDS R01NS130044, NIDA R01DA056599, NIDA R21DA055846, NIDA F31DA062445, NINDS F31NS143421, NIDA F32DA053099, NIDA F32DA055458, NIDA F31DA057795, NINDS F31NS125927, NIDA T32DA028874, NINDS RF1NS126073), the Howard Hughes Medical Institute, the Whitehall Foundation, and the Tito’s Love Research Fund.

Some authors are inventors on a provisional patent application through the University of Pennsylvania and Stanford University regarding the custom sequences used to develop, and the applications of, synthetic opioid promoters (patent application number: 63/383,462 ‘Human and Murine Oprm1 Promoters and Uses Thereof’).