Biology subjects

Shim, S. W.

Publications and source records attributed to Shim, S. W..

3 recordsLinked to original sources

bioRxiv2025

Spared Nav1.8-Positive Nociceptors Drive Persistent Tactile Hypersensitivity After Sciatic Nerve Crush Injury in Mice

Peripheral nerve injury can lead to chronic mechanical hypersensitivity, yet the severity and persistence of pain are strongly influenced by the extent of axonal damage. Notably, partial sciatic nerve crush injury (PCI) produces persistent tactile hypersensitivity despite a less severe anatomical insult than full crush injury (FCI), yet the identity and post-injury state of the fibers that persist after PCI remain unclear. To define sensory neuron populations contributing to PCI-induced tactile hypersensitivity, we combined fiber-specific transgenic labeling (Thy1-YFP for A{beta} mechanoreceptors and Nav1.8-tdTomato for nociceptors) with pharmacological silencing using QX-314 coapplied with TRPV1 (capsaicin) and TLR5 (flagellin) agonists to selectively manipulate fiber subtypes. At day 7 after PCI, Nav1.8+ nociceptive terminals were still detectable in the hind paw. On day 30, acute silencing of TRPV1+ afferents transiently reduced mechanical hypersensitivity, indicating nociceptor activity in its maintenance. Whole-cell patch-clamp recordings of retrogradely labeled DRG neurons showed that remaining medium-diameter neurons exhibited reduced rheobase and increased action potential firings in response to step current injections. Besides, electrical stimulation of nociceptive fibers increased pERK expression in the spinal dorsal horn, indicating enhanced nociceptive signaling after PCI. Early ablation of TRPV1+ fibers with high-dose capsaicin during degeneration phase prevented the subsequent development of long-term tactile hypersensitivity. Collectively, our results suggest that spared nociceptors after PCI remain sensitized even during nerve repair, driving long-term tactile hypersensitivity. Targeting these spared nociceptive fibers after nerve injury may offer a potential strategy for preventing chronic pain associated with traumatic nerve injury. Graphical Summary O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=131 SRC="FIGDIR/small/687306v1_ufig1.gif" ALT="Figure 1"> View larger version (54K): org.highwire.dtl.DTLVardef@1331beorg.highwire.dtl.DTLVardef@26e75aorg.highwire.dtl.DTLVardef@1ecf05org.highwire.dtl.DTLVardef@a96e0b_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2025

Peripheral Nerve Transection Predominantly Drives Sympathetic Nerve Sprouting in Mouse Dorsal Root Ganglia

Sympathetic sprouting in dorsal root ganglia (DRG) is a feature of sympathetically maintained pain (SMP) following peripheral nerve injury, yet the factors determining its occurrence remain unclear. Here, we compare transection and crush injury models to determine if injury type or site influence sympathetic remodeling and pain. Using TH-IR immunostaining and Phox2b reporter mice to selectively label sympathetic fibers, we found that an L5 spinal nerve transection (SpNT) triggered robust sympathetic fiber sprouting and elevated norepinephrine (NE) levels in the DRG, correlating with a mechanical hypersensitivity reversed by chemical sympathectomy. In contrast, a partial sciatic nerve crush injury (PCI) produced long-lasting mechanical hypersensitivity without sympathetic sprouting or NE elevation and was unaffected by sympathectomy. Importantly, sympathetic sprouting was consistently more pronounced after transection injuries at both spinal and sciatic nerve sites, suggesting that injury type, rather than location, is a dominant factor shaping sympathetic remodeling. These findings establish nerve transection as a key driver of sympathetic sprouting and SMP, whereas crush-induced pain likely involves distinct non-sympathetic mechanisms. This distinction has important implications for pain subtype identification and treatment strategies.

neuroscience↗

bioRxiv2025

NKG2D receptor ligands are cell surface biomarkers for injured murine and human nociceptive sensory neurons

Nociceptors are primary afferent neurons that sense noxious stimuli. They can be activated by tissue injury as well as the accompanying local immune response. We have shown that following nerve injury in mice cytotoxic Natural Killer (NK) cells infiltrate the peripheral nerve and interact with stress-induced ligands of the activating receptor NKG2D (Klrk1). However, the diversity and specificity of NKG2D receptor ligands among sensory neuron subtypes, and translation of this mechanism to humans, remains unknown. We used dorsal root ganglion (DRG) neurons cultured from C57BL/6J mice of both sexes with fluorescently-labelled sensory neuron lineages (Scn10a, Mrgprd, Calca, Trpv1, Th, Thy1), as well as human induced pluripotent stem cell derived (hiPSCd)-sensory neurons after laser ablation, as in vitro models of axonal injury. We assessed expression of NKG2D ligands by quantitative polymerase chain reaction (PCR) corroborated by publicly available RNA sequencing datasets and validated with single-cell PCR. Recombinant NKG2D receptor proteins in live cell-based assays were used to reveal the subcellular membrane localisation of NKG2D ligands with quantification by a semi-automated image analysis. Functional interactions between human NK cells and sensory neurons were confirmed with co-cultures in microfluidic devices. We show that NKG2D ligands are expressed exclusively in unmyelinated DRG neurons after injury. NKG2D-receptors bound to puncta along distal neurites of injured axons enriched predominantly in Mrgprd-expressing non-peptidergic nociceptors. We observed low-level binding of human NKG2D-receptors to neurites of hiPSCd sensory neurons that increased after axonal laser ablation. Degeneration of hiPSCd sensory neurons neurites by interleukin (IL-2) primed human NK cells was prevented by an NKG2D blocking antibody. The induction and enrichment of functional NKG2D receptor ligands selectively on pathological nerve fibres could aid the diagnosis of peripheral neuropathy in chronic pain conditions, and sheds new light on the potential role of nociceptive neurons in regulating the local tissue immune microenvironment.

neuroscience↗