A new wave of research is moving away from numbing the body and toward silencing the emotional suffering of chronic pain, offering hope for a future without addiction.
For millions of people, chronic pain is not just a symptom; it’s a thief. It steals joy, disrupts sleep, strains relationships, and fundamentally alters the course of a life. “Chronic pain impacts quality of life, relationships, general activity, sleep and so many other essential life functions, and often is accompanied with many symptoms such as fatigue and low mood,” explains Dr. Matt Mauck, an anesthesiologist and pain medicine physician at the UNC Hospitals Pain Management Center. For those living in this reality, the search for effective relief is a constant, often desperate, journey.
For decades, the primary tools in the fight against severe pain have been opioids. Medications like oxycodone and tramadol can provide powerful short-term relief, but their long-term use is a tightrope walk over a chasm of tolerance, dependence, and addiction. This high-stakes gamble has left both patients and doctors searching for a better way—a treatment that can soothe the suffering without hijacking the brain’s reward systems. Now, a team of dedicated researchers, backed by a major grant from the National Institutes of Health (NIH), is on the verge of a breakthrough that could fundamentally change how we treat pain.
The Purpose and Problem of Pain
Pain, in its purest form, is a vital survival mechanism. It’s the body’s alarm system, a sharp, unmistakable signal that something is wrong. When you touch a hot stove, that jolt of pain makes you pull your hand away, preventing further tissue damage. This sensory information travels from nerves to the spinal cord and up to the brain, where it blossoms into a conscious, emotional experience. It’s this negative, unpleasant quality that motivates us to protect ourselves.
But what happens when the alarm keeps blaring long after the danger has passed? This is the reality of chronic pain, defined as pain that persists for six months or longer. The protective signal becomes a pathological state, a constant torment disconnected from its original injury.
Pharmaceutical companies have long tried to silence this faulty alarm, but with limited success. Opioids work by binding to receptors throughout the brain, effectively dampening the pain signal but also activating powerful reward circuits, which creates the potential for euphoria and addiction. Other treatments, like local anesthetics, take a sledgehammer approach, blocking all sensation in an area—both painful and normal. The ideal solution has remained elusive: a treatment that can selectively turn down the volume of pain’s suffering, without turning off the sensation entirely or creating a dangerous dependency.
A New Target: Isolating the ‘Ouch’ in the Brain
To find this solution, researcher Gregory Scherrer, PharmD, PhD, and his colleagues asked a revolutionary question: What if we could separate the physical sensation of pain from its emotional unpleasantness? “The fundamental problem is that pain is unpleasant,” says Scherrer. “We are currently working on several drug candidates that can target specific neurons in the brain and turn off the ‘unpleasantness’ of pain, while maintaining sensation in the body.”
For years, the precise location of the neurons responsible for this emotional component of pain was a mystery. “We thought that if we could find these cells somewhere in the brain, we might be able to treat pain in a whole new way,” Scherrer notes. “By targeting these cells, chronic pain would be less unpleasant, but you could still sense that you have a problem.”
After extensive research, his team found them. In a landmark 2019 study published in Science, they pinpointed a specific group of cells in the amygdala, a small, almond-shaped region of the brain known for processing emotions like fear and pleasure. Using miniature microscopes mounted on the heads of mice, the researchers watched the brain in action. As the models experienced a painful stimulus, they saw that out of 17,000 neurons in the amygdala, one specific set of cells consistently lit up. These were the neurons that encoded the negative emotional quality of pain.
From Discovery to Drug Development
Identifying these cells was the ‘where.’ The next challenge was the ‘how.’ To design a drug, scientists needed to find a specific “docking station,” or receptor, on the surface of these neurons that a molecule could bind to. With funding from the NIH’s HEAL (Helping to End Addiction Long-term) Initiative, Scherrer’s team isolated these specific amygdala neurons and used a powerful technique called RNA sequencing to map out their genetic activity. This allowed them to identify unique receptors that could serve as targets for a new class of drugs.
The promise of this approach has attracted significant support. In March, Scherrer’s research received a $12 million U19 grant from the NIH—a prestigious, multi-year award reserved for complex, collaborative projects addressing high-priority public health challenges. This funding has assembled a dream team of experts from the UNC School of Medicine, Stanford University, and the University of California, San Francisco.
Medicinal chemist Jeff Aubé, PhD, and therapeutic drug discovery expert Bryan Roth, MD, PhD, are now working alongside Scherrer to develop and test small molecules, or ligands, that can activate these specific receptors. The team is meticulously designing and refining these drug-like compounds, testing their effectiveness in mouse models and on human amygdala tissue.
While this groundbreaking work is still in the preclinical stages, the path forward is clearer than ever. The team is not just conducting basic science; they are on a mission to create a real-world therapy. “Our goal over the next five years or more is to develop a pain drug candidate and then to file an Investigational New Drug (IND) application with the FDA to begin clinical trials,” Scherrer states. This is the first critical step in bringing a new medication to the patients who need it most.
This research represents a paradigm shift in neuropharmacology. By moving beyond the blunt instruments of the past and targeting the precise neural ensemble that makes pain feel painful, science is opening the door to a future where chronic pain can be managed effectively, safely, and without the devastating risk of addiction.
References
Corder, G., Ahanonu, B., Grewe, B. F., Wang, D., Schnitzer, M. J., & Scherrer, G. (2019). An amygdalar neural ensemble that encodes the unpleasantness of pain. Science, 363(6424), 276–281. https://doi.org/10.1126/science.aap8586
Daniels Rovinsky, K. (2024). New Drug Aims to Block Pain Without Addiction Risks. Neuroscience News. Retrieved from https://neurosciencenews.com/pain-neuropharmacology-non-addictive-29605/
