Pathogenic Mechanism of Dry Eye–Induced Chronic Ocular Pain and a Mechanism-Based Therapeutic Approach

PURPOSE: Dry eye–induced chronic ocular pain is also called ocular neuropathic pain. However, details of the pathogenic mechanism remain unknown. The purpose of this study was to elucidate the pathogenic mechanism of dry eye–induced chronic pain in the anterior eye area and develop a pathophysiology-based therapeutic strategy. METHODS: We used a rat dry eye model with lacrimal gland excision (LGE) to elucidate the pathogenic mechanism of ocular neuropathic pain. Corneal epithelial damage, hypersensitivity, and hyperalgesia were evaluated on the LGE side and compared with the sham surgery side. We analyzed neuronal activity, microglial and astrocytic activity, α(2)δ–1 subunit expression, and inhibitory interneurons in the trigeminal nucleus. We also evaluated the therapeutic effects of ophthalmic treatment and chronic pregabalin administration on dry eye–induced ocular neuropathic pain. RESULTS: Dry eye caused hypersensitivity and hyperalgesia on the LGE side. In the trigeminal nucleus of the LGE side, neuronal hyperactivation, transient activation of microglia, persistent activation of astrocytes, α(2)δ–1 subunit upregulation, and reduced numbers of inhibitory interneurons were observed. Ophthalmic treatment alone did not improve hyperalgesia. In contrast, continuous treatment with pregabalin effectively ameliorated hypersensitivity and hyperalgesia and normalized neural activity, α(2)δ–1 subunit upregulation, and astrocyte activation. CONCLUSIONS: These results suggest that dry eye–induced hypersensitivity and hyperalgesia are caused by central sensitization in the trigeminal nucleus with upregulation of the α(2)δ–1 subunit. Here, we showed that pregabalin is effective for treating dry eye–induced ocular neuropathic pain even after chronic pain has been established.