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

Abstract

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