Researchers from The University of Texas at Dallas, in collaboration with international partners, have identified the molecular signature of "sleeping" nociceptors—sensory neurons that are typically unresponsive to touch or pressure but play a significant role in neuropathic pain. The study was published on February 4 in the journal Cell.
Dr. Ted Price, Ashbel Smith Professor of neuroscience at UT Dallas and co-author of the study, explained the significance: "We know from direct human physiological evidence that these cells are important in neuropathic pain," said Price, who also directs the Center for Advanced Pain Studies at UT Dallas. "Now we can identify them at the gene-expression level with an astonishing degree of detail. This will allow researchers to start working on targets to manipulate those cells, which could bring about very exciting developments in the future."
Sleeping nociceptors are found in the dorsal root ganglia near the base of the spine and can become spontaneously active, leading to persistent pain without clear external triggers. These neurons are considered major contributors to neuropathic pain conditions such as diabetic neuropathy, postherpetic neuralgia, and fibromyalgia.
"Active sleeping nociceptors have been found in people with diabetic neuropathy, postherpetic neuralgia and fibromyalgia," Price said. "There are also scores of neuropathic pain studies that found no cause. If you were going to highlight any type of sensory neuron as the biggest culprit for the spontaneous, shooting pain that neuropathy patients have, it's these sleeping nociceptors."
The research was led by Dr. Angelika Lampert from RWTH Aachen University in Germany. Her team used high-resolution recordings and genetic analysis techniques to identify sleeping nociceptors among other nerve cells. Initial experiments involved pig dorsal root ganglia due to their similarity with human tissue; subsequent cross-species analyses confirmed shared molecular markers between pigs and humans.
The study identified specific markers such as the oncostatin M receptor and neuropeptide somatostatin present on these neurons. According to Lampert: "Our work establishes a new conceptual framework for understanding the emergence of neuropathic pain at the molecular level, opening concrete perspectives for the development of targeted therapies."
Dr. Shreejoy Tripathy from the University of Toronto led bioinformatic integration efforts linking functional properties with gene expression profiles: "This collaboration produced a Rosetta stone for pain research, matching the electrical fingerprint of sleeping nociceptors to a specific genetic signature," Tripathy said.
Lampert added: "Now that we have all the information about the different genes expressed in sleeping nociceptors, we can really start to search for an entrance point to drive them back to normal."
Marisol Mancilla Moreno from UT Dallas contributed spatial sequencing data highlighting gene activity patterns within cell types. Price noted plans for further drug discovery efforts based on this comprehensive dataset: "We now hope to start a drug discovery project to try to silence these cells," he said. "The dataset we've generated on the molecular characteristics of these cells is so comprehensive that the modeling is going to be extremely instructive."
The research benefited from contributions by members of NIH's PRECISION Network (Program to Reveal and Evaluate Cells-to-gene Information that Specify Intricacies, Origins, and Nature), which focuses on addressing chronic pain and opioid addiction challenges.
"The PRECISION Network has generated invaluable human data that was essential to this project," Price said. He credited collaborative leadership across institutions for advancing scientific understanding: "Everybody involved in this project is very open and interested in making collaborative scientific advancements. Everybody totally bought in, thanks to great leadership from Angelika at the top of the project."
Lampert emphasized interdisciplinary teamwork: "When you realize the kind of team you need to assemble to answer these questions, you turn to the best people you can find at each portion of the project - collaboration partners with whom you know you can push projects and with whom you enjoy working. The success of the study relies on the close integration of specialized centers, like UT Dallas'. This work demonstrates the power of interdisciplinary and international cooperation."
Additional authors included faculty and researchers affiliated with Harvard Medical School; King's College Hospital (London); German Center for Neurodegenerative Diseases; Heidelberg University; University of Bonn; as well as several others from UT Dallas.
Funding came from multiple sources including grants provided by U.S., Canadian, German governmental agencies as well as private foundations.
