Researchers found that neurons release an enzyme, VLK, that activates pain signaling from outside the cell—an unexpected mechanism.

Removing VLK dulled pain in mice, while adding heightened it, all without impairing normal movement. This suggests a safer way to treat pain without targeting risky receptors inside neurons. The discovery also provides new clues about memory, learning, and how brain cells strengthen their connections.

Breakthrough in How Neurons Trigger Pain Signaling

Researchers at Tulane University, working with collaborators from eight other institutions, have identified a previously unknown way that nerve cells communicate. The discovery may reshape how scientists understand pain and could guide the development of safer, effective treatments.

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In the study, led by Matthew Dalva, director of the Tulane Brain Institute and professor of cell and molecular biology in the School of Science and Engineering, along with Ted Price of the University of Texas at Dallas, the team found that neurons can release an enzyme outside the cell that activates pain signaling after an injury. Their findings, published inSciencealso offer fresh insight into how brain cells strengthen connections involved in learning and memory.

An Enzyme That Activates Pain From Outside the Cell

“This finding changes our fundamental understanding of how neurons communicate,” Dalva said. “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 researchers showed that nerve cells use an enzyme called vertebrate lonesome kinase (VLK) to interact in the space surrounding neurons. By altering proteins in this area, VLK influences how signals move between cells.

VLK: A Newly Revealed Messenger Between Neurons

“This is one of the first demonstrations that phosphorylation can control how cells interact in the extracellular space,” Dalva said. “It opens up an entirely new way of thinking about how to influence cell behavior and potentially a simpler way to design drugs that act from the outside rather than having to penetrate the cell.”

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The team found that active neurons release VLK, which strengthens the function of a receptor tied to pain, learning and memory. When researchers removed VLK from pain-sensing neurons in mice, the animals did not experience typical post-surgical pain but still behaved and sensed their environment normally. Supplying extra VLK increased pain responses.

Boosting and Blocking VLK Shows Powerful Effects on Pain

“This study gets to the core of how synaptic plasticity works — how connections between neurons evolve,” said Price, director of the Center for Advanced Pain Studies, professor of neuroscience at the University of Texas at Dallas’ School of Behavioral and Brain Sciences and a co-corresponding author of the study. “It has very broad implications for neuroscience, especially in understanding how pain and learning share similar molecular mechanisms.”

Dalva added that these findings highlight a promising path for influencing pain pathways by targeting enzymes such as VLK instead of blocking NMDA receptors, which play an important role in communication between nerve cells but can lead to serious side effects when interfered with.

A Safer Pathway for Targeting Pain Without Harsh Side Effects

The finding also provides one of the first examples of how to control interactions between cell-surface proteins outside the cell, which may simplify drug development and reduce off-target effects, since the drug would not enter the cell, he said.

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Next steps are to determine whether this is a mechanism specific to just a few proteins or part of a broader, underappreciated aspect of biology, and, if so, whether it could reshape treatment approaches for neurological and other diseases, Dalva said.

The research was conducted in collaboration with Dalva, Price, and colleagues at The University of Texas Health Science Center at San Antonio, The University of Texas MD Anderson Cancer Center, the University of Houston,Princeton Universitythe University of Wisconsin-Madison,New York UniversityGrossman School of Medicine, and Thomas Jefferson University.

A Major Multi-University Collaboration Unlocks New Biology

“Our findings were only possible through this kind of collaboration,” Dalva said. “By combining Tulane’s expertise in synaptic biology with the strengths of our partners, we were able to reveal a mechanism that has implications not just for pain, but for learning and memory acrossspecies.”

Reference: “The synaptic ectokinase VLK triggers the EphB2–NMDAR interaction to drive injury-induced pain” 20 November 2025,Science.
DOI: 10.1126/science.adp1007

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The research was supported by grants 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 theNational Institutes of Health. Co-first authors of the paper include Dr. Sravya Kolluru, Dr.

Praveen Chander and Dr. Kristina Washburn, all members of The Dalva Lab at Tulane.

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