A team of scientists from Tulane University and eight partner institutions has identified a previously unknown way that nerve cells communicate to trigger pain. In a study published in Science on November 20 2025, the researchers show that nerve cells can release an enzyme outside the cell that activates pain after injury. The discovery offers new insight into how brain cells strengthen their connections during learning and memory and could lead to safer, more effective treatments for pain.
How the enzyme works
The study was co‑led by Matthew Dalva, the Phyllis M. Taylor Presidential Chair in Brain Science at Tulane and director of the Tulane Brain Institute, and Ted Price of the University of Texas at Dallas. Their team found that neurons release an enzyme called vertebrate lonesome kinase (VLK) into the extracellular space. Once outside, VLK modifies proteins on the surface of neighbouring cells to turn on pain signalling without disrupting normal movement or sensation.
Dalva said the discovery fundamentally changes how neuroscientists think about cell‑to‑cell communication. “We’ve discovered that an enzyme released by neurons can modify proteins on the outside of other cells to turn on pain signaling — without affecting normal movement or sensation”. The team noted that this is one of the first examples showing that phosphorylation events outside cells can control how cells interact and may allow drugs to act from the outside rather than having to penetrate the cell.
Experiments in mice and implications for drugs
To examine VLK’s effect on pain, researchers manipulated VLK levels in mice. When they removed VLK from pain‑sensing neurons, the animals did not feel the usual pain after surgery but continued to move and sense normally. Adding extra VLK had the opposite effect, increasing pain responses. Price, director of the Center for Advanced Pain Studies at UT Dallas, said the study “gets to the core of how synaptic plasticity works — how connections between neurons evolve” and has broad implications for understanding how pain and learning share similar molecular mechanisms.
Dalva suggested that targeting enzymes like VLK could provide a safer way to modulate pain pathways. Unlike drugs that block NMDA receptors, molecules that regulate communication between nerve cells but can cause serious side effects, therapies acting on VLK would operate outside the cell and might therefore reduce off‑target effects. The ability to influence interactions between cell‑surface proteins externally could simplify drug development.
Next steps and collaboration
The researchers plan to investigate whether VLK is unique to a handful of proteins or part of a broader and underappreciated aspect of biology. If the mechanism is widespread, it could reshape treatments for neurological and other diseases, Dalva said.
The study was conducted in partnership with scientists from the University of Texas Health Science Center at San Antonio, UT MD Anderson Cancer Center, the University of Houston, Princeton University, the University of Wisconsin‑Madison, New York University Grossman School of Medicine and Thomas Jefferson University. Dalva highlighted that the discovery would not have been possible without such collaboration, noting that combining Tulane’s expertise in synaptic biology with the strengths of these partners allowed the team to “reveal a mechanism that has implications not just for pain, but for learning and memory across species”.
Funding for the research came from the National Institute of Neurological Disorders and Stroke, the National Institute on Drug Abuse and the National Center for Research Resources — all part of the U.S. National Institutes of Health. Co‑first authors of the Science paper include Kolluru Srikanth, Praveen Chander and Halley Washburn, all members of the Dalva Lab at Tulane.
