Breaking the Wall of Non-Addictive Pain Relief

Breaking the Wall of Non-Addictive Pain Relief

Global Call 2026 Finalist Interview: Life Sciences

Gregory Corder is an Associate Professor of Psychiatry at the University of Pennsylvania. His laboratory combines systems neuroscience, molecular engineering, computational behavior, and translational pharmacology to reveal how brain circuits generate pain and analgesia. His team develops cell-type-specific viral tools and gene therapies aimed at producing precise, durable, and non-addictive treatments for chronic pain.

Which wall does your research or project break?  

For more than a century, effective pain relief has forced patients and physicians into a devastating trade-off: medicines powerful enough to relieve severe pain can also suppress breathing, produce tolerance and create the risk of addiction. This wall persists partly because conventional analgesics act broadly throughout the brain and body. They reach the neural cells that relieve suffering, but also many other cells responsible for dangerous side effects.

Our research asks whether these two actions can be separated. Instead of treating pain as a single sensory signal, we focus on the brain circuits that make pain feel distressing, threatening and impossible to ignore. This affective dimension is particularly important in chronic pain, when an initially protective warning can become a persistent state of suffering.

To study this dimension objectively, we created a deep-learning platform that analyzes natural behavior in freely moving animals. Rather than relying only on simple withdrawal reflexes, the traditional standard in preclinical pain research, the system identifies patterns of ongoing behavior that reflect pain-related internal states and their relief by analgesics.

We then combined these measurements with brain imaging, molecular profiling and causal genetic experiments to identify a precise population of opioid-sensitive neurons in the anterior cingulate cortex. These cells proved to be critical for morphine’s ability to reduce the unpleasantness of pain.

Finally, we transformed that biological insight into a synthetic gene therapy that can selectively control this opioid-responsive cell population on demand. In preclinical models, activating the therapy reproduced key pain-relieving effects of morphine without administering an opioid throughout the body. The wall we seek to break is therefore not simply the shortage of new painkillers. It is the assumption that effective pain relief must remain inseparable from the systemic risks of opioid drugs.

What is the main goal of your research or project?  

Our goal is to create precise, controllable and non-addictive treatments for chronic pain by targeting the specific brain cells that generate pain-related suffering.

Pain is not merely the detection of injury. It is a multidimensional experience that includes sensation, emotion, motivation and the urgent drive to protect the body. Existing pain medicines generally act on receptors distributed across many organs and brain regions. This broad pharmacology can reduce pain, but it can also interfere with breathing, reward, alertness and other essential functions.

We are developing a different therapeutic strategy. First, we use artificial intelligence to measure complex, spontaneous patterns of behavior that more closely capture the ongoing burden of pain than conventional reflex tests. We align these behavioral states with recordings from individual neurons to determine which brain circuits track the emergence and relief of pain.

Using this approach, we identified opioid-sensitive neurons in the anterior cingulate cortex that are central to the affective and motivational dimensions of pain. We demonstrated that opioid receptors in this region are necessary and sufficient for an important component of morphine analgesia. In other words, we located a cellular entry point through which morphine can make pain less distressing.

We then engineered a synthetic genetic targeting system inspired by the biology of the μ-opioid receptor. This system delivers a controllable inhibitory receptor specifically to opioid-responsive cortical neurons. A separately administered activating medicine can then regulate those cells when relief is needed, reproducing key analgesic actions of morphine without repeatedly exposing the entire brain and body to an opioid.

The long-term goal is to build a new form of precision neurotherapeutics: treatments selected according to the circuit and cell type producing a patient’s symptoms. Rather than broadly suppressing pain signaling, we aim to intervene at the neural source of persistent suffering while preserving protective sensation and minimizing addiction and respiratory risks.

What impact does your research or project have on society?

Chronic pain affects hundreds of millions of people and is among the leading causes of disability worldwide. It disrupts sleep, employment, mobility, relationships and mental health. Yet the therapeutic choices remain deeply inadequate. Many patients receive medicines that offer limited relief, produce intolerable side effects or lose effectiveness over time. Opioids can be indispensable for severe pain, but their widespread actions create risks of respiratory depression, dependence, misuse and fatal overdose. Our work offers a path beyond the false choice between uncontrolled pain and dangerous systemic medication. The immediate scientific impact is a new way to understand and measure pain. By combining deep-learning analysis of natural behavior with real-time recordings of brain activity, we can study ongoing pain-related states rather than relying primarily on simple reflexes. This may improve the translational relevance, reproducibility and efficiency of preclinical drug development, helping researchers identify treatments that address the dimensions of pain that matter most to patients. The therapeutic impact is the demonstration that a powerful drug such as morphine does not need to be imitated everywhere it acts. Its beneficial effect can potentially be reconstructed within a precisely defined neural population. Our synthetic gene-therapy approach turns opioid-responsive cells into an address for targeted, on-demand treatment while avoiding repeated systemic opioid exposure. More broadly, this work advances a new model of precision medicine for disorders of the brain. Instead of organizing treatment only around a molecular receptor or a diagnostic label, therapies could be designed around the particular cell type and circuit responsible for a disabling symptom. Substantial development and safety testing will be required before this strategy can be evaluated clinically. Nevertheless, the underlying principle could ultimately transform how society treats chronic pain: preserving the lifesaving value of analgesia while separating it from the biological mechanisms that make today’s opioids so dangerous.

What advice would you give to young scientists or students interested in pursuing a career in research, or to your younger self starting in science?

As a university student, I was initially drawn to philosophy of mind. I was fascinated by questions about consciousness: How does the brain transform physical signals and seemingly inert information into the richness of perception, emotion and subjective experience? How do we construct a meaningful internal world from electrical and chemical activity? Those questions led me to neuroscience and created a deep need to understand the relationship between brain, behavior and conscious experience at a fundamental level.

I began with very broad ambitions. Over time, I learned that grand questions become scientifically tractable when they are broken into precise, experimentally testable problems without losing sight of why they matter. In our laboratory, this has meant developing new technologies to measure complex pain-related behavior, identify the specific cells and circuits that shape unpleasant perceptions, and control physical processes in the brain in ways that alter mental experience. What began as an abstract question about how the brain creates conscious states can now be applied toward the tangible goal of alleviating human suffering.

I would encourage young scientists to pursue this connection between fundamental curiosity and meaningful application. Learn one field deeply, but remain willing to cross disciplinary boundaries when the question demands it. Our work has required neuroscience, philosophy, artificial intelligence, molecular biology, viral engineering and behavioral science.

Finally, do not be afraid of questions that initially seem too large. Let them provide direction, while allowing rigorous experiments to determine each next step. Failed experiments and rejected ideas are not detours from science; they are part of its structure. The goal is not to avoid being wrong, but to create tools and experiments that allow nature to show you something more interesting than what you originally imagined.