Abstract

Nerve injury causes neuropathic pain and multilevel nerve barrier disruption. Nerve barriers consist of perineurial, endothe- lial and myelin barriers. So far, it is unclear whether resealing nerve barriers fosters pain resolution and recovery. To this end, we analysed the nerve barrier property portfolio, pain behaviour battery and lipidomics for precursors of specialized pro-resolving meditators (SPMs) and their receptors in chronic constriction injury of the rat sciatic nerve to identify tar- gets for pain resolution by resealing the selected nerve barriers. Of the three nerve barriers—perineurium, capillaries and myelin—only capillary tightness specifically against larger molecules, such as fibrinogen, recuperated with pain resolution. Fibrinogen immunoreactivity was elevated in rats not only at the time of neuropathic pain but also in nerve biopsies from patients with (but not without) painful polyneuropathy, indicating that sealing of the vascular barrier might be a novel approach in pain treatment. Hydroxyeicosatetraenoic acid (15R-HETE), a precursor of aspirin-triggered lipoxin A4, was specifically upregulated at the beginning of pain resolution. Repeated local application of resolvin D1-laden nanoparticles or Fpr2 agonists sex-independently resulted in accelerated pain resolution and fibrinogen removal. Clearing macrophages (Cd206) were boosted and fibrinolytic pathways (Plat) were induced, while inflammation (Tnfα) and inflammasomes (Nlrp3) were unaffected by this treatment. Blocking TAM receptors (Tyro3, Axl and Mer) and tyrosine kinase receptors linking haemostasis and inflammation completely inhibited all the effects. In summary, nanoparticles can be used as transporters for fleeting lipids, such as SPMs, and therefore expand the array of possible therapeutic agents. Thus, the Fpr2–Cd206–TAM receptor axis may be a suitable target for strengthening the capillary barrier, removing endoneurial fibrinogen and boosting pain resolution in patients with chronic neuropathic pain.

Document Type

Article

Publication Date

2025

Notes/Citation Information

© The Author(s) 2024

Digital Object Identifier (DOI)

https://doi.org/10.1007/s00401-024-02840-9

Funding Information

Open Access funding enabled and organized by Projekt DEAL. This study was supported by the German Research Founda- tion Clinical Research Group ResolvePAIN KFO5001 – 42650386, Ri 817/15–1 – 433191715 and SFB 1039/Z01 as well as Evangelisches Studienwerk Villigst and DAAD. PVM received support from the Craig H Neilsen Foundation and the Department of Neurosurgery from the UK.

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