Topical Administration of the Kappa Opioid Receptor Agonist Nalfurafine Suppresses Corneal Neovascularization and Inflammation

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Abstract Corneal neovascularization (CNV) causes higher-order aberrations, corneal edema, ocular inflammation, and corneal transplant rejection, thereby decreasing visual acuity. Here, we investigated the effects of topical administration of the kappa opioid receptor agonist nalfurafine (TRK-820) on CNV. To induce CNV, intrastromal corneal sutures were placed on the corneal stroma of BALB/c mice for 2 weeks. Nalfurafine (0.1 µg/2 μL/eye) was topically administered to the cornea once or twice a day after CNV induction. The CNV score, immune cell infiltration, and mRNA levels of angiogenic and pro-inflammatory factors in neovascularized corneas were evaluated using slit-lamp microscopy, immunohistochemistry, flow cytometry, and polymerase chain reaction. The mRNA expression of the kappa opioid receptor gene Oprk1 was significantly upregulated following CNV induction. Topical administration of nalfurafine twice a day significantly suppressed CNV and lymphangiogenesis, as well as reduced the mRNA levels of angiogenic and pro-inflammatory factors in the neovascularized corneas. Moreover, nalfurafine administration twice a day reduced the numbers of CD45+ infiltrating leukocytes and interferon-γ-producing CD4+ T cells in the neovascularized corneas. Thus, we demonstrated that topical administration of nalfurafine suppressed local CNV in a mouse model along with the activation of KOR. Therefore, nalfurafine may be useful for preventing and controlling CNV in humans.

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