How neuropathic pain and the skin are linked

Neuropathic pain affects about 10% of the population and 20–30% of patients with diabetes mellitus [1]. Chronic itch is one of the most common complaints in dermatological practice, and the same thin nerve fibers of the skin mediate it. A special population — mechanoinsensitive C-fibers (CMi), which researchers call "sleeping" nociceptors — normally does not respond to mechanical stimulation but actively reacts to chemical signals: capsaicin, adenosine triphosphate (ATP), histamine, and inflammatory mediators [1]. In neuropathic pain, spontaneous activity is recorded precisely in these fibers [2], and some CMi fibers are histamine-sensitive and linked to itch [3]. Until now, "sleeping" nociceptors lacked reliable molecular markers, which hampered the study of itch and pain mechanisms and the search for targeted therapies [1].

An international team of researchers set out to link the functional properties of CMi fibers to their molecular profile. To do this, the authors first studied how each nerve cell conducts electrical signals and then determined which genes are active in it (its transcriptome). This combined approach is called Patch-Seq. The work was performed on neurons of porcine dorsal root ganglia — a large animal model whose skin contains fibers with properties close to human CMi; mice lack such fibers in the skin [1]. The resulting picture was compared with atlases of human and other species' neurons, and the authors then tested the key hypothesis in healthy people.

Key results

To find a molecular candidate for "sleeping" nociceptors, the authors used a two-step approach: first they characterized nerve cells in detail — their electrical properties and the set of active genes — and then tested how the key ligand of the identified receptor affects these fibers in humans. The results of both steps are presented below.

Analysis of nerve cells

The authors studied 267 porcine neurons. After quality control, they included 226 cells in the analysis. In addition, they analyzed transcriptomes from 2176 neuronal nuclei. This made it possible to identify 16 types of dorsal root ganglion neurons.

• The candidate for "sleeping" nociceptors was the C-OSMR-SST population. These cells carry the oncostatin M receptor (OSMR) and produce somatostatin (SST).
• They also contain a set of molecules associated with increased nerve-fiber sensitivity: the histamine receptor HRH1, the interleukin-31 receptor IL31RA, and the kinase JAK1. The authors called it the "sensitization repertoire".
• In terms of electrical characteristics, these cells matched "sleeping" nociceptors: with repeated stimulation, their signal gradually slowed; they responded better to sinusoidal stimuli and did not respond to high-frequency stimulation.
• C-OSMR-SST cells had the highest expression of the sodium channel SCN11A (Nav1.9). In addition, they showed the longest action potential duration — 4.26 ms versus 3.34 ms on average for C-fibers [1].

Testing the findings in humans

The authors then tested how oncostatin M affects skin nerve fibers in humans. Oncostatin M is the ligand for the OSMR receptor; it was administered intradermally at 500 ng in 20 µL. Using microneurography in 7 participants, we studied 60 C-fibers: 25 mechanoinsensitive CMi and 35 mechanosensitive C-fibers (CM).

• Oncostatin M specifically changed the electrical properties of CMi fibers: it reduced the slowing of signal conduction during repeated stimulation characteristic of control injections. No such effect was found for CM fibers (p = 0.0154 for CMi).
• During the first 15 minutes, combined administration of oncostatin M and histamine enhanced the axon-reflex flare compared with histamine alone.
• Between 1 and 24 hours, oncostatin M itself caused delayed redness in all 7 participants [1].

These results are consistent with previously published data that oncostatin M can sensitize sensory neurons in inflammatory pruritus [4].

Safety and subjective sensations

Importantly, no changes in subjective perception were reported: quantitative psychophysical testing showed no significant changes in pain, itch, or mechanical sensitivity (von Frey filament and brush tests) within 24 hours after injection. Most CMi fibers remained mechanoinsensitive; only two fibers developed a slight response to mechanical stimulation after oncostatin M administration [1]. The article does not provide systematic data on adverse events, so the absence of described side effects should not be interpreted as proven safety.

Study limitations

This is a fundamental laboratory study with an exploratory human phase, not a clinical trial. The 7 participants included the researchers themselves (self-experimentation), and the sample size was not calculated in advance. Cellular experiments were performed in vitro — on cultured neurons, which could alter gene expression; the selection was biased toward small neurons. The role of Nav1.9 was confirmed by correlation analysis and a computational model, but not by direct intervention. In addition, OSMR is also expressed in another population — C-OSMR-GFRA1/2 — and SST was detected inconsistently by different methods [1].

From molecular targets to clinical practice: a dermatologist's perspective

The study showed that CMi fibers carry receptors associated with itch and inflammatory skin sensitivity: HRH1, IL31RA and JAK1. Therefore, the results are directly related to how itch, redness, and pain can form upon activation of cutaneous nerve endings. The JAK signaling pathway is already used to treat dermatoses accompanied by itch; in particular, abrocitinib has been studied in prurigo nodularis and chronic pruritus of unknown origin [5]. The authors suggest that intervention in the OSMR/JAK1 pathway may affect not only inflammation but also the sensitization of CMi fibers [1].

In addition, the study sheds light on the nature of vascular reactions. The enhancement of the axon-reflex flare with oncostatin M confirms that local skin hyperemia may be driven by activation of mechanoinsensitive fibers [1]. Understanding that different pathways and fiber types mediate redness, itch, and pain gives specialists a reliable tool for more accurate assessment of patient complaints and critical analysis of scientific data on skin sensitivity.

At the same time, the fundamental nature of the discovery requires a balanced interpretation. The results do not provide grounds to change current protocols for aesthetic procedures: the authors did not test injection techniques, topical cosmetic products, or the management of procedural complications. Before direct clinical recommendations appear, these mechanisms need confirmation in patients with chronic itch and pain. However, even today the work shapes a modern view of the skin's sensory system: behind the familiar symptoms of hyperemia, itch and pain lie fundamentally different neuronal mechanisms, and targeted modulation of them opens a new chapter in dermatology.

References

1. Körner J., Howard D., Solinski H.J. et al. Molecular architecture of human dermal sleeping nociceptors. Cell 2026; 189(6): 1820–1835.e22.
2. Kleggetveit I.P., Namer B., Schmidt R. et al. High spontaneous activity of C-nociceptors in painful polyneuropathy. Pain 2012;153(10): 2040–2047.
3. Schmelz M., Schmidt R., Bickel A., Handwerker H.O. Specific C-receptors for itch in human skin. J Neurosci 1997; 17(20): 8003–8008.
4. Tseng P.Y., Hoon M.A. Oncostatin M can sensitize sensory neurons in inflammatory pruritus. Sci Transl Med 2021; 13(619): eabe3037.
5. Kwatra S.G., Bordeaux Z.A., Parthasarathy V. et al. Efficacy and safety of abrocitinib in prurigo nodularis and chronic pruritus of unknown origin: a nonrandomized controlled trial. JAMA Dermatol 2024;  160(7): 717–724.