A biomarker for neuropathic pain: Determining the molecular identity of silent nociceptors.

• Applicants: Professor Dr. Ingo Kurth; Professorin Dr. Angelika Lampert; Professorin Dr. Barbara Namer
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Molecular Biology and Physiology of Neurons and Glial Cells
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 501806838

With this proposal we aim to identify a biomarker for silent nociceptors, a specific class of nerve fibers underlying neuropathic pain. This chronic pain condition presents a major health burden and treatment often shows very limited success. Silent nociceptors are mechano-insensitive C-fibers (CMi-fibers), which are located in the human skin and can only be activated by strong electrical pulse stimulation or following sensitization. Recently, we identified that in human microneurography (MNG) recordings of CMi-fibers a sine wave stimulation succeeds to activate these fibers with much lower stimulation intensity than what is needed for square pulse activation. This specific functional marker now offers the long longed-for opportunity to finally find a biomarker for this disease-relevant fiber type. With the here proposed experiments we aim to identify the ion channel composition that identifies CMi-fibers as such. To this end, we will use MNG recordings on human subjects to specify a CMi-fiber-specific stimulation pattern which we will then transfer to dissociated primary sensory neurons with whole-cell patch-clamp recordings. As mice lack CMi-fibers in the skin, we use pigs as a model, as they were shown to have a very similar dermal innervation to humans. Following in-depth sinus and square pulse stimulation of freshly dissociated pig sensory neurons the target cell population will be subjected to single-cell next-generation sequencing (PatchSeq) to identify (ion channel) genes which determine the molecular identity of CMi-fiber-like neurons. Once identified, siRNAs directed against marker genes will be expressed in pig sensory neurons and, for back translation, in human iPS-cell derived sensory neurons. The molecular profiles are matched with single-cell sequencing data from human and porcine sensory neurons to recognize these cells in the native tissues.With the here proposed experiments it will be possible to identify the long desired biomarker for human silent nociceptors. Knowing their specific ion channel and overall molecular composition, it will be possible to understand – and hopefully modify – spontaneous CMi-fiber activity, which means a decisive step forward in the treatment of neuropathic pain.

• DFG Programme: Research Grants