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<p>Peripheral inflammation is known to enhance pain sensitivity through nociceptive pathways, but its impact on large-diameter myelinated fibers, which mediate touch and proprioception, is less understood. Here, we examined the temporal dynamics of large fiber (Aα/β) excitability in a mouse model of Complete Freund’s Adjuvant (CFA)-induced hind paw inflammation, integrating behavioral, electrophysiological, proteomic, and immune analyses. CFA induced a biphasic modulation of large fiber function, with early hypoexcitability on day 1 followed by hyperexcitability on day 7, temporally aligned with thermal hypersensitivity. Proteomic analysis of sciatic nerve tissue on day 7 revealed upregulation of immune-related proteins, including CD45, providing proteomic evidence of local nerve inflammation. Systemic cytokines and paw skin thrombin activity showed transient elevations at early time points. In vitro, lipopolysaccharide-stimulated Schwannoma-derived cells modulated thrombin activity and altered expression of complement- and inflammation-associated genes. These findings demonstrate that peripheral inflammation dynamically modulates large fiber excitability alongside intrinsic neural and systemic immune responses, highlighting the importance of considering multi-level neuro-immune interactions in models of peripheral nerve function.</p>

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Biphasic modulation of large-fiber excitability accompanied by dynamic nerve-intrinsic immune activation following CFA-induced peripheral inflammation in mice

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年4月17日

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  • Shani Berkowitz,
  • Valery Golderman,
  • Zehavit Goldberg,
  • Anastasia Yerushkin,
  • Omer Goldberg,
  • Joab Chapman,
  • Amir Dori,
  • Nicola Maggio,
  • Tamar Ziv,
  • Jérôme Joël Devaux,
  • Efrat Shavit-Stein

摘要

Peripheral inflammation is known to enhance pain sensitivity through nociceptive pathways, but its impact on large-diameter myelinated fibers, which mediate touch and proprioception, is less understood. Here, we examined the temporal dynamics of large fiber (Aα/β) excitability in a mouse model of Complete Freund’s Adjuvant (CFA)-induced hind paw inflammation, integrating behavioral, electrophysiological, proteomic, and immune analyses. CFA induced a biphasic modulation of large fiber function, with early hypoexcitability on day 1 followed by hyperexcitability on day 7, temporally aligned with thermal hypersensitivity. Proteomic analysis of sciatic nerve tissue on day 7 revealed upregulation of immune-related proteins, including CD45, providing proteomic evidence of local nerve inflammation. Systemic cytokines and paw skin thrombin activity showed transient elevations at early time points. In vitro, lipopolysaccharide-stimulated Schwannoma-derived cells modulated thrombin activity and altered expression of complement- and inflammation-associated genes. These findings demonstrate that peripheral inflammation dynamically modulates large fiber excitability alongside intrinsic neural and systemic immune responses, highlighting the importance of considering multi-level neuro-immune interactions in models of peripheral nerve function.