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

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.