Molecular architecture of human dermal sleeping nociceptors.

Summary

Using Patch-seq and cross-species transcriptomics, the authors identify OSMR and SST as molecular markers of human mechano-insensitive C-fiber nociceptors and demonstrate selective modulation by oncostatin M in human volunteers. This defines a long-sought human targetable nociceptor subtype and provides translational evidence for neuromodulatory strategies in neuropathic pain.

Key Findings

• Identified OSMR and SST as marker genes for mechano-insensitive C-fiber nociceptors (CMis) using Patch-seq.
• Selective modulation of CMis demonstrated in healthy human volunteers by dermal oncostatin M (OSMR ligand).
• Cross-species integration (pig/human) and spatial transcriptomics established the molecular architecture of human dermal CMis.

Clinical Implications

OSMR/SST may enable patient stratification and development of targeted analgesics or neuromodulation for neuropathic pain. Oncostatin M–OSMR signaling emerges as a candidate pathway for intervention.

Limitations

• Sample sizes for human functional testing are not detailed and may be limited.
• Clinical efficacy and safety of targeting OSMR/SST pathways remain untested in patients with neuropathic pain.

Future Directions

Prospective interventional trials targeting OSMR signaling in neuropathic pain; development of selective agonists/antagonists; biomarker-driven stratification in analgesic trials.