Abstract：
UNASSIGNED: Neuropathic corneal pain (NCP) is a new and ill-defined disease characterized by pain, discomfort, aching, burning sensation, irritation, dryness, and grittiness. However, the mechanism underlying NCP remain unclear. Here, we reported a novel rat model of primary NCP induced by long ciliary nerve (LCN) ligation. After sustained LCN ligation, the rats developed increased corneal mechanical and chemical sensitivity, spontaneous blinking, and photophobia, which were ameliorated by intraperitoneal injection of morphine or gabapentin. However, neither tear reduction nor corneal injury was observed in LCN-ligated rats. Furthermore, after LCN ligation, the rats displayed a significant reduction in corneal nerve density, as well as increased tortuosity and beading nerve ending. Long ciliary nerve ligation also notably elevated corneal responsiveness under resting or menthol-stimulated conditions. At a cellular level, we observed that LCN ligation increased calcitonin gene-related peptide (neuropeptide)-positive cells in the trigeminal ganglion (TG). At a molecular level, upregulated mRNA levels of ion channels Piezo2, TRPM8, and TRPV1, as well as inflammatory factors TNF-α, IL-1β, and IL-6, were also detected in the TG after LCN ligation. Meanwhile, consecutive oral gabapentin attenuated LCN ligation-induced corneal hyperalgesia and increased levels of ion channels and inflammation factors in TG. This study provides a reliable primary NCP model induced by LCN ligation in rats using a simple, minimally invasive surgery technique, which may help shed light on the underlying cellular and molecular bases of NCP and aid in developing a new treatment for the disease.
摘要：
■神经性角膜疼痛（NCP）是一种以疼痛为特征的新型疾病，不适,疼痛,灼烧感,刺激,干燥度,和坚韧不拔。然而,NCP的潜在机制尚不清楚.这里,我们报道了一种新型大鼠经长睫状神经（LCN）结扎诱导的原发性NCP模型。持续LCN结扎后，大鼠角膜机械和化学敏感性增加，自发眨眼,和畏光，通过腹腔注射吗啡或加巴喷丁改善。然而,在LCN结扎的大鼠中未观察到泪液减少或角膜损伤。此外，LCN结扎后，大鼠角膜神经密度显著降低,以及增加弯曲和串珠神经末梢。在静息或薄荷醇刺激的条件下，长睫状神经结扎也显着提高了角膜反应性。在细胞水平，我们观察到LCN连接会增加三叉神经节（TG）中降钙素基因相关肽（神经肽）阳性细胞。在分子水平上,上调离子通道Piezo2、TRPM8和TRPV1的mRNA水平，以及炎症因子TNF-α，IL-1β,和IL-6也在LCN连接后的TG中检测到。同时,连续口服加巴喷丁可以减轻LCN结扎诱导的角膜痛觉过敏，并增加TG中离子通道和炎症因子的水平。本研究提供了一种可靠的大鼠LCN结扎诱导的原代NCP模型，微创手术技术,这可能有助于阐明NCP的潜在细胞和分子基础，并有助于开发该疾病的新疗法。
