Acute Hyperalgesia and Delayed Dry Eye After Corneal Abrasion Injury

Abstract

Corneal nerves mediate pain from the ocular surface, lacrimation, and blinking, all of which protect corneal surface homeostasis and help preserve vision. Corneal nerve density correlates with neuropathic pain states and is used as an assessment of small fiber neuropathies. Because pain, lacrimation and blinking are rarely assessed at the same time, it is not known if their regulatory mechanisms have similar temporal dynamics after acute corneal injury. We examined changes in corneal nerve density, evoked and spontaneous pain, and ocular homeostasis in Sprague-Dawley male rats after a superficial epithelial injury with heptanol that acutely abolished nerve endings within the central cornea. Despite a profound loss of epithelial nerve endings, pain was transiently enhanced after abrasion injury, while basal tear production was normal. We found no relationship between epithelial nerve density and pain or homeostatic responses. Axotomy following corneal abrasion increased expression of both ATF3 (a nerve injury marker) and CGRP (a nociceptive peptide) in trigeminal ganglia 24 hours after injury. These molecular changes were absent on the contralateral side, despite reductions in corneal epithelial nerve density in the uninjured eye. ATF3 and CGRP levels in trigeminal ganglion were normal at one week post-injury when pain responses were normal. In contrast, CGRP was upregulated in peripheral corneal endings one week after injury, when dry eye symptoms emerged. Our results demonstrate dynamic trafficking of CGRP within trigeminal sensory nerves, with elevations in the ganglion correlated with pain behaviors and elevations in peripheral endings correlated with dry eye symptoms. peer-reviewed)

Effects of corneal injury on ciliary nerve fibre activity and corneal nociception in mice: A behavioural and electrophysiological study

“…The second model, corneal scraping, corresponds to an axotomy of the corneal sensory axon terminals at the basal epithelial cell layer (Liang et al, 2012). In this model, we performed experiments 24 hr after nerve axotomy because the pain peaks occurred at 24 hr after epithelial debridement (Green, Alvarez, & Levine, 2015;Hegarty, Hermes, Morgan, & Aicher, 2018) and in commonly used animal models of neuropathic pain, pain behaviours appear within the first 12-48 hr after injury (Bennett & Xie, 1988;Kim & Chung, 1992;Seltzer, Dubner, & Shir, 1990). IVCM images showed the presence of numerous inflammatory cells 24 hr after corneal scraping, which is in accordance with other studies (Li, Xie, Strong, & Zhang, 2007;Li, Zhang, Xie, Strong, & Zhang, 2017).…”

Resveratrol increases tear production and spontaneous ocular pain after corneal abrasion in male, but not female, rats using a preclinical model of photorefractive keratectomy (PRK)

“…Tear production was assessed using the phenol thread test (Zone-Quick, Oasis Medical, Gendora, CA) as described previously (Aicher et al, 2015;Hegarty et al, 2018). This test is equivalent to the Schirmer's test (Vashisht and Singh, 2011) used clinically to measure tear production.…”

“…One week after corneal abrasion and after final behavioral assessments, rats were overdosed with sodium pentobarbital (150 mg/kg) and perfused transcardially through the ascending aorta with 10 ml of heparinized saline (1000 units/ml) followed by 600 ml of 4% paraformaldehyde in 0.1 M phosphate buffer, pH 7.4 (PB) (Hegarty et al, 2018;Hegarty et al, 2017). The eyes were enucleated immediately after perfusion and placed in PB.…”

“…We have previously described a corneal abrasion model that simulates the initial step in the PRK procedure in which the corneal epithelium is removed and the corneal sensory nerves are severed in the abraded area (Hegarty et al, 2018). Furthermore, the behavioral, homeostatic and morphological effects of this corneal abrasion model are similar to the chief complaints of acute pain, photophobia and tear dysfunction from post-operative PRK patients.…”

Vers une meilleure compréhension des douleurs oculaires chroniques

“…En outre, une axotomie des nerfs cornéens induit une augmentation de l'expression à la fois d'ATF3 et du CGRP dans le GT ipsilatéral à la lésion 24 heures après l'axotomie. Bien que les niveaux d'ATF3 et du CGRP recouvrent des niveaux d'expression de base une semaine après la lésion dans le GT, en revanche, le CGRP est fortement augmenté dans les terminaisons cornéennes (Hegarty et al, 2018). Ainsi, ces acteurs proinflammatoires pourraient jouer un rôle important non seulement dans la sensibilisation périphérique, mais également dans le transfert de l'information nocicep-…”