Traumatic peripheral nerve injuries are at high risk of neuropathic pain for which novel effective therapies are urgently needed. Preclinical models of neuropathic pain typically involve irreversible ligation and/or nerve transection (neurotmesis). However, translation of findings to the clinic has so far been unsuccessful, raising questions on injury model validity and clinically relevance. Traumatic nerve injuries seen in the clinic commonly result in axonotmesis (ie, crush), yet the neuropathic phenotype of “painful” nerve crush injuries remains poorly understood. We report the neuropathology and sensory symptoms of a focal nerve crush injury using custom-modified hemostats resulting in either complete (“full”) or incomplete (“partial”) axonotmesis in adult mice. Assays of thermal and mechanically evoked pain-like behavior were paralleled by transmission electron microscopy, immunohistochemistry, and anatomical tracing of the peripheral nerve. In both crush models, motor function was equally affected early after injury; by contrast, partial crush of the nerve resulted in the early return of pinprick sensitivity, followed by a transient thermal and chronic tactile hypersensitivity of the affected hind paw, which was not observed after a full crush injury. The partially crushed nerve was characterized by the sparing of small-diameter myelinated axons and intraepidermal nerve fibers, fewer dorsal root ganglia expressing the injury marker activating transcription factor 3, and lower serum levels of neurofilament light chain. By day 30, axons showed signs of reduced myelin thickness. In summary, the escape of small-diameter axons from Wallerian degeneration is likely a determinant of chronic pain pathophysiology distinct from the general response to complete nerve injury.

Nociceptors are known to directly recognize bacterial cell wall components or secreted toxins, thereby leading to pain induced by bacterial infection. However, direct activation of nociceptors by bacterial metabolites remains unclear although bacteria produce numerous metabolites related to health and disease. In this study, we investigated whether and how a common bacterial metabolite, indole, which is produced by normal microflora of the gastrointestinal tract and oral cavity, can directly activate nociceptive sensory neurons. We found that indole elicits calcium response and evokes inward currents in subsets of dorsal root ganglia (DRG) neurons. Intraplantar (i.pl.) injection of indole produced nocifensive behaviors in adult mice, which were enhanced in complete Freund’s adjuvant–induced chronic inflammatory condition. Indole increased calcitonin gene-related peptide release in DRG neurons, and i.pl. injection of indole increased hind paw thickness, suggesting its role in generation of neurogenic inflammation. These in vitro and in vivo indole-induced responses were pharmacologically blocked by transient receptor potential ankyrin 1 (TRPA1) antagonist, HC-030031, and significantly abolished in TRPA1 knockout (KO) mice, indicating that indole targets TRPA1 for its action in DRG neurons. Nocifensive licking behavior induced by the injection of live Escherichia coli was significantly decreased in tryptophanase mutant (TnaA KO) E. coli-injected mice that lack indole production, further supporting the idea that bacteria-derived indole can induce pain during infection. Identifying the mechanism of action of indole through TRPA1 provides insights into bacteria–neuron interactions and the role of bacterial metabolites in pain signaling, especially in inflammation-accompanied bacterial infection.

This study investigated whether tongue motor loss induced by bilateral transection of the hypoglossal nerves (Hx) alters anxiety- and/or depression-like behaviors in rats and examined the associated neuroendocrine changes. Male Sprague–Dawley rats underwent Hx or sham surgery and were evaluated in the ambulatory activity, elevated plus maze, forced swim, and sucrose preference tests at different postoperative time points. Neuroendocrine parameters were assessed by plasma corticosterone assay, quantitative real-time PCR, Western blot analysis, and adrenal histology. At two weeks after surgery, Hx rats exhibited anxiety-like behavioral changes in the elevated plus maze and increased immobility with reduced struggling in the forced swim test, consistent with a depression-like behavior. Reduced sucrose intake was observed at earlier postoperative stages, suggesting early anhedonia-like behavior. Hx rats also showed chronically increased plasma corticosterone levels, adrenocortical hypertrophy, and decreased hippocampal glucocorticoid receptor expression. These findings highlight a potential oral–systemic interaction in which loss of oral motor function alters neuroendocrine homeostasis and emotional regulation.

Pain often accompanies tissue injury and inflammation. However, in certain inflammatory contexts like periodontitis, nociceptive signaling is paradoxically suppressed. The mechanisms underlying this analgesic state remain poorly understood. Here, we investigated whether and how Porphyromonas gingivalis (Pg) interacts with sensory neurons to induce analgesia in models of inflammatory pain. Exposure to live Pg reversed inflammatory thermal and mechanical hypersensitivity without altering local inflammation or nerve innervation. This effect required direct physical contact mediated in part by an integrin α ₅ -FimA interface and gingipain protease activity and was not reproduced by heat-killed bacteria, protease-deficient mutants, or Pg-derived extracellular vesicles. At the neuronal level, Pg contact induced membrane hyperpolarization, reduced excitability of sensory neurons, and suppressed release of the nociceptive neuropeptide calcitonin gene-related peptide (CGRP). Proteomic and functional analyses identified downregulation of Fxyd2, a regulatory subunit of the Na ⁺ /K ⁺ -ATPase, linking altered ionic homeostasis to nociceptor silencing. These findings define a contact-dependent mechanism that actively suppresses peripheral pain signaling during inflammation.