(Press-News.org) Philadelphia—A preclinical study uncovered a new gene therapy that targets pain centers in the brain while eliminating the risk of addiction from narcotics treatments, a breakthrough which could provide hope for the more than 50 million Americans living with chronic pain.
Dealing with chronic pain can feel like listening to a radio where the volume is stuck at maximum volume, and no matter what you do, the noise never seems to dull or lessen. Opioid medications, like morphine, work by turning down the volume, but they also affect other parts of the brain, sometimes leading to dangerous side effects or even addiction.
The potential new gene therapy is akin to a volume knob that only turns down the pain station and leaves everything else untouched, according to research from teams at the University of Pennsylvania Perelman School of Medicine and School of Nursing, along with collaborators at Carnegie Mellon University and Stanford University, published today in Nature.
“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.”
An AI-driven blueprint for non-addictive, brain circuit-specific pain medicine
Morphine is a narcotic derived from opium with a high potential for abuse because patients who use it can develop tolerance, requiring higher and higher doses to achieve the same reduction in pain. By imaging brain cells that act as pain trackers, the team uncovered new insight into how morphine eases suffering.
From there, they built a mouse-model behavioral platform driven by artificial intelligence (AI) that tracks natural behaviors, creates a readout of pain levels, and helps gauge how much treatment is needed to alleviate the pain.
This readout, used as a sort of map, allowed the team to design a targeted gene therapy that mimics morphine’s beneficial effects but avoids its addictive ones while delivering an “off switch” specifically for pain felt in the brain. When activated, this switch provides durable pain relief without affecting normal sensation or triggering reward pathways that can lead to 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.
Easing one crisis without fueling another
The results are the culmination of more than six years of investigation powered by a National Institutes of Health New Innovator Award that allowed Corder and his colleagues to research the mechanisms of chronic pain.
In 2019, 600,000 deaths were attributed to drug use, with 80 percent of those related to opioids. Nearly half of Philadelphians who responded to a 2025 Pew survey reported knowing someone with opioid use disorder (OUD). One-third knew someone who had died as the result of an overdose.
Chronic pain, known to some as a ‘silent epidemic’ impacts approximately 50 million Americans, costing upward of $635 million annually in direct medical expenses and indirect costs from lost productivity, including missed work and reduced earning capacity. Now, these findings have the potential to help ease that pain—or, turning down the noise—for some, should the science hold through additional testing and into clinical trials.
The team is moving forward with Michael Platt, PhD, the James S. Riepe University Professor, Professor of Neuroscience, Professor of Psychology, on the next phase of work as a hopeful bridge toward future 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’). See the full paper for additional disclosures.
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