Select noxious stimuli induce changes on corneal nerve morphology

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The cornea is a unique and specialized barrier that protects vulnerable ocular tissues from environmental insults. The cornea is densely innervated with nerves that are tasked with maintaining the integrity of the corneal surface by detecting potentially harmful stimuli and evoking behavioral and reflexive responses to neutralize the stimulus (Shaheen, Bakir, & Jain, 2014). The innervating corneal nerves are primarily nociceptors and these can be classified based on the categories of stimuli that activate the nerve. Corneal nerves can be found that respond selectively to cold stimuli while others respond selectively to mechanical forces, but the majority are classified as polymodal nociceptors that respond to a wide variety of stimuli such as heat, chemical irritants, and inflammatory mediators (Belmonte, Acosta, & Gallar, 2004). The corneal nerves contain receptors that transduce environmental stimuli into nerve activity, including TRPV1 channels that transduce noxious heat stimuli and TRPM8 channels that transduce noxious cold stimuli (Alamri, Bron, Brock, & Ivanusic, 2015; Guo, Vulchanova, Wang, Li, & Elde, 1999; Hiura & Nakagawa, 2012; Ivanusic, Wood, & Brock, 2013; Murata & Masuko, 2006; Nakagawa, Hiura, Mitome, & Ishimura, 2009; Parra et al., 2010). Corneal nerves are also thought to contain osmotic receptors that are sensitive to hypertonic conditions in tears (Chao et al., 2016), although the molecular transducer has not been definitively identified. Polymodal nociceptors are presumed to contain more than one type of these molecular transducers (Chao et al., 2016). Activity from corneal nerves is transmitted via the ophthalmic branch of the trigeminal nerve to the trigeminal brainstem and supraspinal substrates of nociception, resulting in the perception of ocular pain (Aicher, Hegarty, & Hermes, 2014; Aicher, Hermes, & Hegarty, 2013; Belmonte et al., 2004; Hegarty, Hermes, Largent‐Milnes, & Aicher, 2014; Hegarty, Tonsfeldt, Hermes, Helfand, & Aicher, 2010; Marfurt & Del Toro, 1987; Meng & Bereiter, 1996).
Ocular pain can result from corneal exposure to environmental irritants, corneal injuries stemming from accidents, vision correction surgery such as LASIK or general surgery (Altinors, Bozbeyoglu, Karabay, & Akova, 2007; Ang, Dartt, & Tsubota, 2001; Grixti, Sadri, & Watts, 2013). Ocular pain is also seen in chronic conditions such as dry eye disease and normal aging (Chao et al., 2016; Lemp, 2008). Advances in imaging technologies have allowed direct assessment of corneal nerve morphology with the underlying assumption that changes in nerve morphology may be associated with changes in sensory function. For example, in vivo confocal microscopy of corneal nerves is emerging as a clinical assessment tool to measure changes in corneal nerve density and morphology as a means of evaluating neuropathic changes to the corneal nerve population resulting from disorders such as diabetes or dry eye disease (Cruzat, Pavan‐Langston, & Hamrah, 2010; Kallinikos et al., 2004). Some studies have observed correlations between nerve morphology and pain states (Altinors et al., 2007; Cruzat et al., 2010; Dworkin, 2002; Theophanous, Jacobs, & Hamrah, 2015; Tuisku, Konttinen, Konttinen, & Tervo, 2008); however, these studies provide conflicting and paradoxical results that make it difficult to establish a direct relationship between corneal nerve integrity and ocular pain.
The effects of chronic disease on corneal nerve morphology may be confounded with changes in nerve morphology induced by acute corneal stimulation. The effect of topical chemical stimulation on the structural integrity of the corneal nerves themselves has only been examined in a few studies (Bates et al., 2010; Harti, Sharkey, & Pierau, 1989; Hirata, Mizerska, Marfurt, & Rosenblatt, 2015). In this study, we quantitatively measured the effects of behaviorally noxious chemical stimuli on the corneal innervation.
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