Dry eye disease and neuropathic corneal pain : translational exploration of novel therapeutic and diagnostic strategies

Dry eye disease (DED) is a multifactorial disease of the ocular surface, often leading to chronic ocular pain, with limited efficient treatment options. In numerous cases, it can be associated with neuropathic corneal pain (NCP), even more difficult to manage. Treating NCP is highly challenging, and there is still a current lack of available topical nerve-targeted treatment to alleviate ocular pain. This is very relevant as it represents a debilitating condition that can dramatically affect the quality of life of the patient. The present translational research project aims to improve the management of DED-related neuropathic pain by increasing our understanding of DED pathophysiology, by investigating new treatment options for DED-related pain and by trying to improve the diagnosis of DED-related neuropathic pain. The corneal epithelium is the most densely innervated tissue by nociceptors in the human body, with 600 terminals/mm2. It is an excellent tissue to study the morphological and functional properties of peripheral nociceptors as well as neuro-immune interactions, not only because of its huge nerve density, but also because of its easy accessibility. In this line, preclinical studies from our team have focused on the elucidation of cellular and molecular mechanisms of analgesia following the targeting of the ocular opioid system for the management of corneal pain. The first part of the PhD project explored the therapeutic potential of targeting the corneal opioid system using topical treatments in two animal models of acute inflammatory pain and of chronic pain associated with DED. We provided the first demonstration that mu opioid receptor (MOR) is expressed in mouse corneal nerves. We also detected the expression of MOR mRNA in most polymodal neurons and revealed it was overexpressed in the V1 branch of the TG in both models of ocular pain. Furthermore, we showed that topical ocular administration of DAMGO, a MOR agonist, significantly reduced both mechanical and chemical corneal hypersensitivity in both models of corneal pain. Overall, these data provide evidence that activation of corneal opioid receptors could constitute a therapeutic approach for the treatment of corneal pain. The second part of the project assessed potential biomarkers of DED-related NCP in human patients and novel phenotyping strategies to improve the diagnosis and thus management of NCP in DED in clinical practice. We conducted a retrospective case-control clinical study evaluating patient clinical and in vivo confocal microscopy (IVCM) imaging data from a cohort of patients with corneal neuropathic pain in two etiological subsets of DED: auto-immune-related DED (AIDE) and primary meibomian gland dysfunction (MGD)-related DED. IVCM images analysis revealed that AIDE-related NCP patients displayed increased nerve tortuosity and number of microneuromas whereas MGD-related NCP patients had reduced nerve density and increased number, perimeter, and area of microneuromas compared with healthy controls. Furthermore, a higher number of microneuromas was found in MGD-related NCP compared to AIDE-related NCP or painless MGD. Additional IVCM-based parameters described microneuromas, such as area and perimeter could actually be useful to discriminate between etiological subsets of DED, an initial step towards better patient phenotyping and thus better personalized pain management. In conclusion, this research project explored new avenues for the management of DED with the hope of eventually helping to improve the quality of life of patients suffering from this highly burdensome ocular disease.