Cell-Specific Gene Therapy May Offer Chronic Pain Relief
A cell-specific gene therapy shows promise in mice as an alternative to opioids for treating chronic pain.
A cell-specific gene therapy may provide relief from chronic pain, a study in mice shows.
Chronic pain is one of the most common reasons that adults seek medical care. In 2023, nearly a quarter of adults in the US experienced chronic pain, with 8.5% of adults experiencing high-impact chronic pain that frequently limited life or work activities.
Opioids like morphine are used to reduce the brain’s perception of pain, but they come with risks of addiction and potentially severe side effects. They act on widely expressed targets in the brain, namely the μ-opioid receptor. Understanding how opioids alter pain-sensing neuron dynamics is key to developing safer pain treatments.
Two types of pain
Pain can be described as nociceptive or neuropathic. Nociceptive pain occurs after an injury or tissue damage and involves nerve receptors called nociceptors, whereas neuropathic pain stems from damage to the nervous system itself.
A gene therapy for chronic pain
In mice, cortical activity patterns shift following nerve injury—reflecting how chronic pain emerges. These activity patterns can be reversed by morphine.
Previous research had identified that the anterior cingulate cortex (ACC) is a key brain region involved in the emotional and motivational dynamics of chronic pain. It guides behavioral choices to avoid harmful stimuli.
New research has shown that within the ACC, a population of neurons encodes pain-related behaviors. These neurons offer an avenue for developing a new class of analgesics that reduce pain.
The researchers used nociceptive activity-dependent tagging to pinpoint a pain “hotspot” in the ACC, followed by in situ hybridization and single-nucleus RNA sequencing to identify the neuronal cell types that express the µ-opioid receptor.
They then designed a chemogenetic gene therapy to silence the µ-opioid receptor-expressing neurons in the ACC.
Chemogenetics
Using chemogenetics, cells can be selectively activated or silenced by a ligand after they are modified to express an engineered receptor.
The gene therapy contained a synthetic mouse µ-opioid receptor promoter region to selectively target neurons expressing the µ-opioid receptor. In these cells, the gene therapy drives the expression of hm4-DREADD—a commonly-used chemogenetic receptor. When the hM4–DREADD ligand, deschloroclozapine, is introduced, these cells are silenced.
In mice, administration of the gene therapy and its activating drug ligand after nerve injury reduced pain-related behaviors and suppressed widespread nociceptive responses throughout the brain.
Changing the way we measure pain
The current standard of measuring pain is a reflexive withdrawal response, i.e., watching for a flinch after a subject is poked with a pin or blunt object.
“It’s artificial,” said Dr. Eric Yttri, an associate professor of biological sciences and part of the research team. “People with chronic back pain or nerve dysfunction aren't spending their days getting poked with pins. They’re trying to live. They’re walking differently, rubbing a sore shoulder, avoiding the stairs, moving slower. That’s where the real story of pain is told. It’s not in a reflex, but in the movements of daily life.”
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For the new research, Yttri and colleagues used AI algorithms to create a framework that describes pain-related movement in mice across six behaviors—staying still, walking, rearing, grooming, and licking the left or right hindpaw. The platform enabled the researchers to assess whether treatment was easing pain, rather than dulling sensation.
How the gene therapy compares to opioids
The researchers compared pain-related behaviors in mice with nerve injury after the administration of gene therapy or morphine. The gene therapy was found to mimic the effects of opioids for treating chronic neuropathic pain, and in some cases, provided superior relief against the behavioral features of chronic pain.
The reduction of behaviors linked to distress or avoidance indicates that although pain may be present, it is no longer overwhelming.
“We’re treating the emotional experience of pain,” Yttri said. “You still feel the touch, the pressure, the reality of the injury. But the agony that keeps you from working or living—that’s what we’re aiming to erase.”
The gene therapy could be adapted for non-invasive delivery, the researchers report in the paper, offering hope for safer and more effective alternatives to opioids.
Reference: Oswell CS, Rogers SA, James JG, et al. Mimicking opioid analgesia in cortical pain circuits. Nature. 2026;649(8098):938-947. doi: 10.1038/s41586-025-09908-w
This article is a rework of a press release issued by Carnegie Mellon University. Material has been edited for length and content.
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