The molecular characteristics of dormant nociceptors provide intriguing new avenues for pain relief.
A groundbreaking study conducted by researchers from the Centre for Addiction and Mental Health (CAMH) in Canada, alongside the Institute of Neurophysiology at Uniklinik RWTH Aachen in Germany, has unveiled the intricate molecular identity of what are known as sleeping nociceptors. These specialized nerve cells typically remain inactive, unresponsive to touch or pressure, yet can become hyperactive and contribute to persistent pain sensations. The results of this significant research will be published on Wednesday, February 4th, in the prestigious journal Cell.
It is estimated that around ten percent of individuals worldwide endure neuropathic pain—pain arising from nerve damage—which is often linked to unusual activity in these sleeping nociceptors. In scenarios of chronic pain, these neurons can spontaneously start sending signals, resulting in continuous discomfort even in the absence of any external stimuli. While their functional behavior has been documented for quite some time, the specific genetic makeup of these cells has remained largely ambiguous. Although researchers could identify sleeping nociceptors through their electrical activity, understanding the genes that were activated within these cells was a mystery. This lack of a genetic profile hindered the development of targeted pain management strategies.
An international team of researchers, spearheaded by Univ.-Prof. Dr. Angelika Lampert, who directs the Institute of Neurophysiology at Uniklinik RWTH Aachen, along with Dr. Shreejoy Tripathy, a senior scientist at CAMH and an associate professor at the University of Toronto, has made strides in bridging this critical knowledge gap. By simultaneously measuring the electrical properties and genetic expression of individual neurons, they succeeded in pinpointing the specific genes that characterize sleeping nociceptors. Their success hinged on their ability to interpret the distinct 'languages' of neuronal electrical activity and genetics. Co-first author Dr. Jannis Körner, a clinician-scientist at Uniklinik, utilized a state-of-the-art technique called Patch-Seq, which merges electrophysiology with single-cell genetic sequencing, to monitor the electrical responses of individual neurons. The data collected were then analyzed through comprehensive bioinformatics methods led by co-first author Derek Howard, a CAMH Research Methods Specialist, under Dr. Tripathy’s guidance.
This remarkable collaboration resulted in what can be likened to a 'Rosetta stone' for pain research, enabling scientists to translate findings from laboratory studies into a better understanding of the biology of sleeping nociceptors in humans. This achievement allowed the research team to assign molecular identities to these nociceptors and identify particular targets for future pain treatments.
In their analyses, the researchers discovered that sleeping nociceptors possess a unique molecular signature, which notably includes components like the oncostatin M receptor (OSMR) and the neuropeptide somatostatin (SST). As Dr. Körner explains, "Our findings also indicate other potential drug targets, such as the ion channel Nav1.9, which exhibits high expression in sleeping nociceptors and is key to their unique electrical functions." In simpler terms, this ion channel likely plays a crucial role in regulating how readily these sleeping nociceptors can become active, and targeting Nav1.9 may pave the way for medications designed to selectively calm these pain-triggering neurons.
Derek Howard adds, "Our bioinformatics studies suggested that OSMR could serve as a marker for sleeping nociceptors; however, that remains a hypothesis until it's rigorously tested. What made our collaboration stand out was our colleagues’ eagerness to take these predictions and validate them experimentally." He further elaborates, "In our concluding set of psychophysics experiments, we demonstrated that oncostatin M, which activates OSMR, specifically interacts with sleeping nociceptors in human skin. This validated our molecular hypotheses directly in human subjects," states Dr. Körner.
This research lays the groundwork for a new conceptual framework aimed at understanding the molecular foundations of neuropathic pain while simultaneously revealing promising opportunities for developing innovative, targeted therapies.
Dr. Angelika Lampert emphasizes the significance of collaborative efforts in this research: "This work underscores the immense potential of interdisciplinary and international collaboration. The success of our study depended on the seamless integration of specialized research centers: while the core experiments took place in Aachen, vital single-cell and spatial transcriptomic analyses were conducted in Mannheim and Dallas." Dr. Tripathy concurs, stating, "It was an honor to be part of such an elite team of experts. This project exemplifies the remarkable achievements possible when diverse scientific insights converge to tackle a shared challenge."
The research was further bolstered by contributions from distinguished pain researchers such as Barbara Namer (now at the University of Würzburg), Jordi Serra (King's College London, UK), Martin Schmelz, Hans-Jürgen Solinski (both from Heidelberg University, Mannheim), Ted Price (University of Texas, Dallas, USA), and William Renthal (Harvard University, USA).
Reference:
Körner, J., et al. (2026). Molecular architecture of human dermal sleeping nociceptors. Cell. DOI: 10.1016/j.cell.2025.12.048. https://www.cell.com/cell/fulltext/S0092-8674(25)01497-7
