Neuropathic Ocular Pain: An Important Yet Underevaluated Feature of Dry Eye

A Galor; RC Levitt; ER Felix; ER Martin; CD Sarantopoulos


Eye. 2015;29(3):301-312. 

In This Article

Environmental Conditions, Inflammation, and Their Effect on Peripheral Corneal Nerves

Environmental Conditions

Many environmental conditions can activate corneal nociceptors and thereby produce dry eye symptoms. Experimentally, the controlled adverse environment (CAE) model has been used both as a screening tool to identify patients susceptible to environmental insults and as a diagnostic tool to test various dry eye therapeutics.[40] For example, 19 dry eye patients and 20 controls were exposed to low humidity for 2 h in the CAE. After exposure, both dry eye patients and controls had significant ocular surface alterations including increased corneal staining, decreased TBUT, and increased matrix metalloproteinase-9 (MMP-9) tear levels.[41] In another study by the same group, similar findings were seen after 20 dry eye patients were exposed to a CAE simulating an in-flight airplane cabin for 2 h.[42] Environmental factors such as high altitude,[43] wind,[15] air pollution,[15,44] volcanic eruption,[45] dust,[46] and chemicals[47,48] have also been associated with transient and/or chronic dry eye. In our study of 3.41 million patients seen in 394 Veteran Affairs (VA) eye clinics within the continental United States, we found that several environmental factors were significantly associated with the risk of a dry eye diagnosis.[49] Among these, air pollution and atmospheric pressure emerged as the most significant predictors. For example, veterans in Chicago and New York City were three to four times more likely to be diagnosed with dry eye as compared with less urban areas with relatively low concentrations of aerosol optical depth (a surrogate marker of air pollution) such as Ukiah (CA, USA).


Adverse environmental conditions and local abnormalities, such as eyelid malposition, may lead to ocular surface damage. This damage to epithelial cells and nociceptors can lead to the release of various inflammatory mediators, such as adenosine triphosphate, prostaglandins (PGs), and substance P, and cause immune cell infiltration (Figure 2).[28] In fact, elevated levels of PGE2 have been found in the tears of dry eye patients as compared with controls.[50] Similarly, mice subjected to adverse environmental conditions also displayed higher cyclooxygenase 2 (COX2) and PGE synthase mRNA levels on the ocular surface.[50] In line with immune cell recruitment, T cells have been found in the conjunctivae[51] and elevated levels of inflammatory cytokines have been found in the tears of dry eye patients.[52,53] Specifically, tear levels of IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-17, and tumor necrosis factor-α (TNF-α) have been found to be elevated in dry eye compared with control subjects.[52,53] Environmental stress can also lead to an increase in reactive oxygen species. For example, oxidative stress-induced lipid peroxidation was increased on the conjunctivae of Sjogren's patients as assessed by detection of hexanoyl-lysine (HEL) and 4-hydroxy-2-nonenal (4HNE) protein adducts.[54] Furthermore, corneal epithelial damage may upregulate nerve growth factor (NGF) and decrease calcitonin gene-related peptide (CGRP) levels.[55–57] Finally, MMP-9 levels have been shown to increase in the tears of dry eye patients.[58,59] In addition to pro-inflammatory mediators, there are anti-inflammatory mediators, such as those derived from omega 3 and 6 fatty acids (ie, resolvins and protectins[60]), and the presence of both pro- and anti-inflammatory mediators are likely important in regulating the signs and symptoms in dry eye.

Figure 2.

A simplified version of the relationship between environmental insults, inflammation, and nociceptor function. Mechanical, chemical, and thermal insults can damage corneal epithelial cells and nociceptors that results in a cascade of inflammatory mediators including adenosine triphosphate (ATP), prostaglandins (PGs), substance P (SP), matrix metalloproteinases (MMPs), reactive oxygen species (ROS), and nerve growth factor (NGF). In addition, there is an influx of immune cells including T cells, macrophages (Mφ), and neutrophils (Nφ). These cells secrete a variety of cytokines (interleukins and tumor necrosis factor (TNF)) that all alter the function of nociceptors. Other mediators, including resolvins and protectins, are involved in ending the inflammatory cascade and restoring nociceptor function. Persistent environmental stress or inflammatory responses can lead to permanent changes in nociceptor function.

Peripheral Sensitization

The above inflammatory environment, along with other stresses such as hyperosmolarity,[61] can affect the function of nociceptors with alterations in ion channel activity (increased sodium and calcium currents at the nociceptor terminal) through changes in gene expression and transcription, as reviewed by Pergolizzi et al[28] and Costigan et al.[62] The resultant phenotypic change of reduced activation thresholds and increased excitability is termed peripheral sensitization (Figure 3).

Figure 3.

(a) Normal nociceptor response to a noxious stimulus is shown. (b) Neuroplasticity in the first-order neuron (peripheral sensitization). In the absence of a stimulus, the cell body and terminal end of the first-order neuron display spontaneous activity that translates into pain sensation. (c) Neuroplasticity in the second-order neuron (central sensitization). In the absence of a stimulus, the cell body of the second-order neuron displays spontaneous activity that translates into pain sensation.

Peripheral sensitization can be reversed after resolution of the inciting stress and normalization of ocular surface inflammation (Figure 2). As noted, a few molecules including resolvins and protectins have been found to promote active receptor-mediated resolution of inflammation.[60] In fact, various animal and human studies have shown that omega 3 fatty acids (from which resolvins and protectins are derived) improved symptoms, signs, and inflammation associated with dry eye.[63–67] This effect is likely mediated through the biosynthetic process of omega fatty acids to resolvins and protectins. For example, neuroprotectin D1 (a product of docosahexaenoic acid (DHA)) was found to be as effective as DHA itself in improving corneal sensitivity and tear production and decreasing neutrophil infiltration after experimental nerve injury.[68] Similarly, resolvin E1 (a product of eicosapentaenoic acid (EPA)) protected the ocular surface from adverse environmental conditions in mice with decreased staining and maintenance of goblet cell density.[69] In the same model, resolvins decreased COX2 expression and inflammatory cells infiltrates.[70] Resolvins also interacted with cytokines by blocking TNF-α-mediated effects in salivary gland tissue.[71] Importantly, the regulation of pro-resolving mediators appear to be influenced by neuronal functioning and may be reduced after neuronal injury and dysfunction associated with a reduction in Netrin-1 affecting resolvin D1 production.[72]