Latent Sensitization in a Mouse Model of Ocular Neuropathic Pain

Abstract

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.

Morphological and Functional Changes of Corneal Nerves and Their Contribution to Peripheral and Central Sensory Abnormalities

“…Furthermore, surgically induced chronic dry eye models obtained after the unilateral removal of extra-orbital lacrimal gland in mice (Yamazaki et al, 2017 ) or after the excision of the extraorbital lachrymal gland and Harderian gland had similar findings (Fakih et al, 2019 ): a reduction in corneal nerve density accompanied with corneal allodynia. Finally, structural abnormalities including a profound loss of nerve density in the sub-basal nerves and increasing of beading and tortuosity of stromal nerve trunks also occurred in a model of corneal injury-induced neuropathic pain (Cho et al, 2019 ; Pham and Bazan, 2020 ).…”

Nicotinamide Riboside Alleviates Corneal and Somatic Hypersensitivity Induced by Paclitaxel in Male Rats

“… 9 Injury is known to cause sprouting. 39 , 40 It is possible that the density of nerves in the subbasal plexus is diminished, yet remaining axons that enter the corneal epithelium sprout after the injury. Corneal epithelium and stromal nerves can reinnervate in the presence of a persistent decrease in the density of the subbasal nerve plexus 40 and references therein.…”

Opioids and Ocular Surface Pathology: A Literature Review of New Treatments Horizons

“…The etiology of neuropathic and chronic pain is associated with the opioid system. In a model of corneal surface injury in mice with change and damage of the corneal nerves, the corneal injury-induced central and peripheral opioid receptor-dependent showed latent sensitization [ 98 ]. Latent sensitization is a long-lasting model of chronic pain in which hyperalgesia is continuously suppressed by the action of opioid receptors.…”