Nerve injury causes neuropathic pain and multilevel nerve barrier disruption. Nerve barriers consist of perineurial, endothelial 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 targets 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.

神经损伤会导致神经性疼痛和多节段神经屏障破坏。神经屏障由神经周围屏障、内皮屏障和髓鞘屏障组成。到目前为止，尚不清楚重新密封神经屏障是否能促进疼痛的消退和恢复。为此，我们分析了大鼠坐骨神经慢性收缩损伤中专业促消退冥想者 （SPM） 前体及其受体的神经屏障特性组合、疼痛行为电池和脂质组学，以确定通过重新密封选定的神经屏障来确定疼痛消退的目标。在三种神经屏障（神经束膜、毛细血管和髓鞘）中，只有专门针对较大分子（如纤维蛋白原）的毛细血管紧密性随着疼痛的缓解而恢复。大鼠的纤维蛋白原免疫反应性不仅在神经性疼痛时升高，而且在患有（但并非没有）疼痛性多发性神经病患者的神经活检中也升高，这表明血管屏障的密封可能是疼痛治疗的一种新方法。羟基二十碳四烯酸 （15R-HETE） 是阿司匹林触发的脂质毒素 A4 的前体，在疼痛缓解开始时特异性上调。重复局部应用含有 resolvin D1 的纳米颗粒或 Fpr2 激动剂，不分性别地导致加速疼痛缓解和纤维蛋白原去除。清除巨噬细胞 （Cd206） 得到增强，纤维蛋白溶解途径 （Plat） 被诱导，而炎症 （Tnfα） 和炎性小体 （Nlrp3） 不受这种治疗的影响。阻断连接止血和炎症的 TAM 受体 （Tyro3 、 Axl 和 Mer） 和酪氨酸激酶受体完全抑制了所有作用。 总之，纳米颗粒可以用作短暂脂质（如 SPM）的转运蛋白，从而扩展可能的治疗剂范围。因此，Fpr2-Cd206-TAM 受体轴可能是加强慢性神经性疼痛患者毛细血管屏障、去除神经内膜纤维蛋白原和促进疼痛缓解的合适靶点。