Modeling Neuropathic Corneal Pain: Pulled Nerve Approach With Elevated Krt16 Gene Expression

Abstract

PURPOSE. Neuropathic corneal pain (NCP) is a debilitating condition affecting millions of people worldwide. Despite their critical importance, currently available animal models for NCP research are limited by complex surgeries with high-risk strategy. To advance fundamental understanding of NCP, we developed a novel rodent model that explores both structural and functional mechanisms of the disease, offering a comprehensive approach. METHODS. By uplifting (2–3 mm transversely) the long ciliary nerve (LCN) with gentle force (0.09 ± 0.02 newton [N]) and pressure (0.18 ± 0.05 MPa), our pulled nerve model mimics human NCP conditions and was investigated alongside normal control, sham control, and full transection groups. Specifically, we quantified the NCP status by establishing a relationship between pain perception and chemical sensitivity, using Stevens’ Power Law concept. RESULTS. Following surgery, the temporal patterns of heightened pain perception showed consistent trends across different stimulus methods, suggesting that von Frey and chemical tests could effectively evaluate pain progression. The discernable differences in Alpha values (exponent) of the pain-perception curves across the normal control, pulled nerve, and full transection groups (0.175 ± 0.035, 0.235 ± 0.015, and 0.275 ± 0.005, respectively) demonstrate the model’s sensitivity to changes in NCP status. Histological analysis revealed LCN elongation, thickening, and corneal alterations in pulled nerve models, with reduced satellite glial cells (SGCs) in trigeminal ganglion compared to the normal control models. Krt16 gene expression was significantly upregulated following pulled nerve surgery. CONCLUSIONS. Our model not only delineates the pathological landscape of NCP but also promises to accelerate the development of targeted therapies. Copyright 2025 The Authors.