Purpose: Chronic ocular pain is poorly understood and difficult to manage. We developed a murine model of corneal surface injury (CSI)–induced chronic ocular neuropathic pain. The study focuses on changes in corneal nerve morphology and associated short- and long-term pain-like behavior after CSI.
Methods: CSI was induced in mice by local application of an alkali solution (0.75 N NaOH). Corneal nerve architecture, morphology, density, and length were studied. Eye-wiping was evaluated before and after CSI in response to hypertonic saline (2 M NaCl). Naltrexone (NTX) or Naloxone-methiodide (NLX-me), opioid receptor antagonists, were given subcutaneously (s.c., 3 mg/kg) or topically (eye drop, 100 μM), and then an eye-wiping test was performed.
Results: CSI caused partial corneal deinnervation followed by gradual reinnervation. Regenerated nerves displayed increased tortuosity, beading, and branching. CSI enhanced hypertonic saline-induced eye-wiping behavior compared to baseline or sham-injury (P < 0.01). This hypersensitivity peaked at 10 days and subsided 14 days after CSI. Administration of NTX, or NLX-me, a selective peripheral opioid antagonist, reinstated eye-wiping behavior in the injury group, but not in the sham groups (P < 0.05).
Conclusions: This study introduces a model of chronic ocular pain and corneal neuropathy following CSI. CSI induces central and peripheral opioid receptor-dependent latent sensitization (LS) that is unmasked by systemic or topical administration of opioid antagonists.
Translational Relevance: This model of chronic ocular pain establishes LS as a new inhibitory mechanism in the oculotrigeminal system and may be used for potential diagnostic and therapeutic interventions for ocular neuropathy.
Digital Object Identifier (DOI)
Supported by the University of Kentucky CTSA Grant KL2 TR001996C (RJCA) and R01NS62306 (BKT).
Cho, Jooyoung; Bell, Nicholas; Botzet, Gregory; Vora, Paras; Fowler, Benjamin J.; Donahue, Renee R.; Bush, Heather M.; Taylor, Bradley K.; and Albuquerque, Romulo J. C., "Latent Sensitization in a Mouse Model of Ocular Neuropathic Pain" (2019). Ophthalmology and Visual Science Faculty Publications. 14.