A novel animal model of neuropathic corneal pain-the ciliary nerve constriction model.

Introduction: Neuropathic pain arises as a result of peripheral nerve injury or altered pain processing within the central nervous system. When this phenomenon affects the cornea, it is referred to as neuropathic corneal pain (NCP), resulting in pain, hyperalgesia, burning, and photoallodynia, severely affecting patients' quality of life. To date there is no suitable animal model for the study of NCP. Herein, we developed an NCP model by constriction of the long ciliary nerves innervating the eye. Methods: Mice underwent ciliary nerve constriction (CNC) or sham procedures. Safety was determined by corneal fluorescein staining to assess ocular surface damage, whereas Cochet-Bonnet esthesiometry and confocal microscopy assessed the function and structure of corneal nerves, respectively. Efficacy was assessed by paw wipe responses within 30 seconds of applying hyperosmolar (5M) saline at Days 3, 7, 10, and 14 post-constriction. Additionally, behavior was assessed in an open field test (OFT) at Days 7, 14, and 21. Results: CNC resulted in significantly increased response to hyperosmolar saline between groups (p < 0.0001), demonstrating hyperalgesia and induction of neuropathic pain. Further, animals that underwent CNC had increased anxiety-like behavior in an open field test compared to controls at the 14- and 21-Day time-points (p < 0.05). In contrast, CNC did not result in increased corneal fluorescein staining or decreased sensation as compared to sham controls (p > 0.05). Additionally, confocal microscopy of corneal whole-mounts revealed that constriction resulted in only a slight reduction in corneal nerve density (p < 0.05), compared to naïve and sham groups. Discussion: The CNC model induces a pure NCP phenotype and may be a useful model for the study of NCP, recapitulating features of NCP, including hyperalgesia in the absence of ocular surface damage, and anxiety-like behavior.

Immunomodulatory Role of Neuropeptides in the Cornea.

The transparency of the cornea along with its dense sensory innervation and resident leukocyte populations make it an ideal tissue to study interactions between the nervous and immune systems. The cornea is the most densely innervated tissue of the body and possesses both immune and vascular privilege, in part due to its unique repertoire of resident immune cells. Corneal nerves produce various neuropeptides that have a wide range of functions on immune cells. As research in this area expands, further insights are made into the role of neuropeptides and their immunomodulatory functions in the healthy and diseased cornea. Much remains to be known regarding the details of neuropeptide signaling and how it contributes to pathophysiology, which is likely due to complex interactions among neuropeptides, receptor isoform-specific signaling events, and the inflammatory microenvironment in disease. However, progress in this area has led to an increase in studies that have begun modulating neuropeptide activity for the treatment of corneal diseases with promising results, necessitating the need for a comprehensive review of the literature. This review focuses on the role of neuropeptides in maintaining the homeostasis of the ocular surface, alterations in disease settings, and the possible therapeutic potential of targeting these systems.

Concurrent ocular pain in patients with neurotrophic keratopathy.

PURPOSE: To illustrate that ocular pain may occur in patients with neurotrophic keratopathy (NK) that typically are thought to lack symptoms of discomfort, and that aa subset of these patients may also present with neuropathic corneal pain (NCP). METHOD: Retrospective Case series of 7 stage 1 NK patients who presented with concurrent ocular pain, as confirmed by clinical examination, proparacaine challenge test, and in vivo corneal confocal microscopy (IVCM). Records were assessed for results of ocular surface disease index (OSDI), pain on visual analog scale (VAS), ocular pain assessment survey (OPAS), best-corrected visual acuity (BCVA), corneal fluorescein staining (CFS) score, and IVCM findings. IVCM findings were compared to that of 20 healthy reference controls. RESULTS: Mean age of patients was 63.7 ± 11.6 (range 44-76) years and 56.9 ± 8.6 (range 42-74) years in reference controls (p = 0.11). At presentation, ocular discomfort was 8.0 ± 1.3 (range 7-10) on VAS and mean OSDI scores were 72.26 ± 6.81 (range 62.50-79.54). Mean BCVA was 20/40, and mean CFS scores were 3.43 ± 0.79 (range 2-4) on the Oxford scale. IVCM analysis showed significant decrease in mean total, main and branch nerve densities in ranges consistent with NK as compared to normal controls (p < 0.001 for all), increased dendritiform cell density in three patients (p < 0.001), and the presence of microneuromas in six of the patients. CONCLUSION: Patients with NK are thought to present with hypoesthesia. However, nerve damage and inflammation, which play a role in the development of NK may result in the development of chronic ocular pain, such as NCP, resulting in potential underdiagnosis of either disease.

Topical Adoptive Transfer of Plasmacytoid Dendritic Cells for Corneal Wound Healing.

Plasmacytoid dendritic cells (pDCs) are crucial for corneal homeostasis through secretion of various anti-angiogenic molecules and growth factors. Due to its avascular nature, only a limited number of adoptively transferred cells home to the cornea, when administered systemically. In addition, local adoptive transfer of cells poses several challenges and the clinical application of commonly used techniques is limited. Herein, we detail a novel approach for local adoptive transfer of pDCs to the cornea for the treatment of corneal wounds. This approach utilizes a commonly used fibrin sealant as a means of transferring previously isolated cells locally on the cornea. The technique is simple, reproducible, and is accompanied with successful transfer and integration of a substantial number of the cells to the cornea. Application of this approach to transfer pDCs promotes corneal wound healing. Furthermore, this technique can be applied for adoptive transfer of any cell of interest to the cornea.