Molecular signature of sleeping nociceptors offers new pain targets

Researchers from the Centre for Addiction and Mental Health (CAMH) and the Institute of Neurophysiology at Uniklinik RWTH Aachen in Germany have deciphered the molecular signature of so-called sleeping nociceptors-a type of pain-sensing nerve cell that normally remains quiet and does not respond to touch or pressure, but can become overactive and drive chronic pain. The findings will be published on Wednedsay, February 4 in the renowned scientific journal Cell.

Approximately ten percent of the population lives with neuropathic (nerve-related) pain, which is frequently associated with abnormal activity of sleeping nociceptors. In chronic pain conditions, these neurons can begin firing on their own, causing ongoing pain even when there is no external trigger. Although their functional properties have been known for many years, their molecular identity remained unclear. Researchers could identify sleeping nociceptors based on how they behave electrically, but they did not know which genes were switched on inside these cells. Without this genetic fingerprint, developing targeted treatments remained out of reach.

An international research team led by Univ.-Prof. Dr. Angelika Lampert (Director of the Institute of Neurophysiology at Uniklinik RWTH Aachen, Germany) and Dr. Shreejoy Tripathy (CAMH Senior Scientist at the Krembil Centre for Neuroinformatics and Associate Professor at University of Toronto), has now closed this key knowledge gap. By measuring both the electrical behaviour and the genetic activity of individual neurons, the researchers were able to identify exactly which genes define sleeping nociceptors. To succeed, the team had to translate between the distinct "languages" of nerve cell electricity and genetics. Co-first author Uniklinik Clinician-Scientist Dr. Jannis Körner recorded the electrical activity of individual neurons using Patch-Seq, a cutting-edge method that combines electrophysiology with single-cell genetic sequencing. These data were then integrated with comprehensive bioinformatics analyses led by co-first author Derek Howard, CAMH Research Methods Specialist under the supervision of Dr. Tripathy.

This collaboration produced a "Rosetta stone" for pain research-a way to translate between these two scientific languages-linking findings from pre-clinical research with the biology of sleeping nociceptors in humans. This allowed the team to assign a molecular identity to sleeping nociceptors and uncover specific targets for future pain therapies.

Molecular hallmarks of sleeping nociceptors

The team's analyses reveal that sleeping nociceptors are defined by a specific molecular signature, which includes, among other components, the oncostatin M receptor (OSMR) and the neuropeptide somatostatin (SST). Co-first author Dr. Körner explains: "The findings also point to additional drug targets, including the ion channel Nav1.9, which was highly expressed in sleeping nociceptors and contributes to their distinctive electrical properties." Put simply, this channel likely helps control how easily sleeping nociceptors become active and targeting Nav1.9 may enable the development of medications that selectively quiet these pain-causing neurons."

Co-first author Derek Howard adds: "Our bioinformatics analyses pointed to OSMR as a marker of sleeping nociceptors, but that's just a prediction until someone tests it. What made this collaboration special was our colleagues' willingness to take that prediction and validate it." "In our final set of psychophysics experiments, we showed that oncostatin M, which activates OSMR, specifically modulates sleeping nociceptors in the human skin. This confirmed our molecular predictions directly in humans," explains co-first author Dr. Körner.

Our work establishes a new conceptual framework for understanding the emergence of neuropathic pain at the molecular level, while at the same time opening concrete perspectives for the development of new, targeted therapies."

Dr. Angelika Lampert, Director of the Institute of Neurophysiology at Uniklinik RWTH Aachen, Germany

Multi-disciplinary international team

Prof. Lampert highlights the importance of the collaboration: "This work demonstrates the power of interdisciplinary and international cooperation. The success of the study relies on the close integration of specialized centers: while the key experiments were performed in Aachen, crucial single-cell and spatial transcriptomic efforts were undertaken in Mannheim and Dallas." Dr. Tripathy adds: "It was a privilege to be part of such an 'all-star' team of experts. This project is a testament to what can be achieved when we combine diverse scientific perspectives to solve a common problem."

The research team was further strengthened by contributions from the groups led by the renowned pain researchers Barbara Namer (now University of Würzburg), Jordi Serra (King's College London, UK), Martin Schmelz and Hans-Jürgen Solinski (Heidelberg University, Mannheim), Ted Price (University of Texas, Dallas, USA), and William Renthal (Harvard University, USA).