Using a Patch-seq approach integrating electrophysiology and transcriptomics across species, the authors identified oncostatin M receptor (OSMR) and somatostatin (SST) as molecular marker genes for human dermal sleeping nociceptors (mechano-insensitive C-fibers, CMis), and showed that intradermal oncostatin M exclusively modulates CMis in healthy human volunteers.
Key Findings
Results
Oncostatin M receptor (OSMR) and somatostatin (SST) were identified as marker genes for mechano-insensitive C-fibers (CMis), the cellular basis of human dermal sleeping nociceptors.
Identification was achieved through a Patch-seq approach combining single-cell transcriptomics with electrophysiological characterization.
Single-nucleus and spatial transcriptomics from pig tissue were integrated with cross-species and human transcriptomic data to validate the markers.
Prior to this study, a molecular marker for mechano-insensitive C-fibers (CMis) in human skin was described as 'elusive.'
CMis are described as displaying ongoing activity in neuropathic pain, which affects approximately 10% of the population.
Methods
CMis were functionally identified in pig sensory neurons using patch clamp electrophysiology with protocols adapted from human microneurography.
The study used pig sensory neurons as a model system for Patch-seq because functional CMi identification required electrophysiological characterization prior to transcriptomic profiling.
Protocols were specifically adapted from human microneurography techniques to classify neurons as mechano-insensitive in the pig preparation.
Single-nucleus and spatial transcriptomics from pig tissue complemented the single-cell Patch-seq data.
Findings were subsequently integrated with cross-species and human transcriptomic datasets to confirm relevance to human biology.
Results
Intradermal injection of oncostatin M, the ligand of OSMR, exclusively modulated CMis in healthy human volunteers.
The experiment was conducted in healthy human volunteers using dermal injection of oncostatin M.
The selective effect on CMis was assessed in vivo, consistent with OSMR being a marker gene specifically enriched in this fiber type.
This finding functionally validated OSMR as a CMi-specific marker at the protein/ligand level, not only at the transcriptomic level.
The exclusivity of the oncostatin M effect on CMis suggests potential for targeted therapeutic strategies aimed at this nociceptor subpopulation.
Conclusions
The molecular architecture of human dermal sleeping nociceptors was characterized, providing a framework for mechanistic insight into neuropathic pain.
Neuropathic pain affects approximately 10% of the population, and sleeping nociceptors (CMis) display ongoing activity in this condition.
The characterization integrates single-cell, single-nucleus, and spatial transcriptomics with functional electrophysiology across species.
The identified markers OSMR and SST provide candidate targets for future therapeutic strategies specifically directed at CMis.
The cross-species integration (pig, human) and use of human microneurography-adapted protocols strengthen the translational relevance of the findings.
What This Means
This research addresses a long-standing challenge in pain biology: identifying the specific type of nerve fiber responsible for a category of chronic pain called neuropathic pain, which affects roughly 1 in 10 people. A particular class of pain-sensing nerve fibers in human skin — called 'sleeping nociceptors' or mechano-insensitive C-fibers (CMis) — becomes abnormally active in neuropathic pain, but until now, no reliable molecular 'tag' existed to identify and target these fibers specifically. The researchers used an innovative technique called Patch-seq, which combines measuring the electrical activity of individual nerve cells with reading their genetic activity at the same time, along with spatial mapping of genes in pig and human tissue, to find genes that uniquely mark these fibers.
The study found that two genes — the oncostatin M receptor (OSMR) and somatostatin (SST) — serve as molecular markers that distinguish sleeping nociceptors from other nerve fiber types. Crucially, when the researchers injected oncostatin M (the natural protein that activates OSMR) directly into the skin of healthy human volunteers, it selectively affected only the CMi fiber type and not other nerve fibers, confirming that this receptor is functionally specific to sleeping nociceptors in living humans.
This research suggests that the molecular identity of human sleeping nociceptors has now been defined for the first time, opening the door to developing treatments that could specifically target these fibers. Because current pain treatments often affect many different nerve fiber types and have broad side effects, a therapy that could selectively quiet only the sleeping nociceptors responsible for neuropathic pain could represent a more precise approach to managing this difficult-to-treat condition.
Körner J, Howard D, Solinski H, Mancilla Moreno M, Haag N, Fiebig A, et al.. (2026). Molecular architecture of human dermal sleeping nociceptors.. Cell. https://doi.org/10.1016/j.cell.2025.12.048