Diabetic keratopathy and treatment by modulation of the opioid growth factor (OGF)-OGF receptor (OGFr) axis with naltrexone: a review.

The Opioid Growth Factor (OGF) – OGF receptors (OGFr) axis plays an important role in the homeostasis and re-epithelialization of the mammalian cornea. This tonically active growth regulatory inhibitory pathway is involved in cell replication, and the endogenous neuropeptide OGF targets cyclin dependent kinase inhibitors, p16 and/or p21. Blockade of OGF-OGFr interfacing by systemic or topical administration of opioid antagonists such as naltrexone (NTX) results in accelerated DNA synthesis, cell replication, and tissue repair. Molecular manipulation of OGFr using sense constructs delays corneal re-epithelialization, whereas antisense constructs accelerated repair of the corneal surface. Corneal keratopathy, a significant complication of diabetes mellitus, is manifested by delays in corneal re-epithelialization following surgery, injury, or disease. Tissue culture studies have shown that addition of NTX stimulates DNA synthesis and explant outgrowth of rabbit corneal epithelium, whereas OGF depresses DNA synthesis and explant outgrowth in a receptor-mediated manner. NTX accelerated corneal re-epithelialization in organ cultures of human and rabbit cornea. Systemic application of NTX to the abraded corneas of rats, and topical administration of NTX to the injured rabbit ocular surface, increased re-epithelialization. Systemic injections or topical administration of NTX facilitates re-epithelialization of the cornea in diabetic rats. Given the vital role of the corneal epithelium in maintaining vision, the frequency of corneal complications related to diabetes (diabetic keratopathy), and the problems occurring in diabetic individuals postoperatively (e.g., vitrectomy), and that conventional therapies such as artificial tears and bandage contact lenses have failed, topical application of NTX merits clinical consideration.

阿片生长因子（OGF） - OGF受体（OGFr）轴在哺乳动物角膜的内稳态和再上皮化中起重要作用。这种具有张力活性的生长调节抑制通路参与细胞复制，内源性神经肽OGF作用于细胞周期蛋白依赖性激酶抑制剂p16和/或p21。通过全身或局部给予阿片拮抗剂如纳曲酮（NTX）阻断OGF - OGFr相互作用，会导致DNA合成加速、细胞复制和组织修复。使用正义构建体对OGFr进行分子操作会延迟角膜再上皮化，而反义构建体则会加速角膜表面的修复。角膜病变是糖尿病的一种重要并发症，表现为手术、损伤或疾病后角膜再上皮化延迟。组织培养研究表明，添加NTX可刺激兔角膜上皮的DNA合成和外植体生长，而OGF以受体介导的方式抑制DNA合成和外植体生长。NTX可加速人和兔角膜器官培养中的角膜再上皮化。对大鼠磨损的角膜全身应用NTX，以及对受伤的兔眼表面局部给予NTX，可增加再上皮化。对糖尿病大鼠全身注射或局部给予NTX可促进角膜再上皮化。鉴于角膜上皮在维持视力方面的重要作用、与糖尿病相关的角膜并发症（糖尿病性角膜病变）的发生频率以及糖尿病患者术后（例如，玻璃体切除术）出现的问题，并且人工泪液和绷带隐形眼镜等常规治疗方法已失败，局部应用NTX值得临床考虑。