Neuropathic pain and dry eye

Abstract

Dry eye is a common, multifactorial disease currently diagnosed by a combination of symptoms and signs. Its epidemiology and clinical presentation have many similarities with neuropathic pain outside the eye. This review highlights the similarities between dry eye and neuropathic pain, focusing on clinical features, somatosensory function, and underlying pathophysiology. Implications of these similarities on the diagnosis and treatment of dry eye are discussed.

Keywords: Dry eye; Genetics; Inflammation; Nerve sensitization; Neuropathic pain; Treatment.

Published by Elsevier Inc.

Figures

Fig. 1

Mechanisms of peripheral sensitization. Injury to epithelial cells results in the release of numerous inflammatory mediators such as bradykinin, prostaglandins (PG), serotonin, and histamine, to name a few. Peripheral nerve terminals have receptors that recognize these inflammatory molecules (5HT for serotonin, H1 for histamine, EP for PG, B2/B1 for bradykinin). Their activation triggers the release of substance P (SP) and calcitonin gene-related peptide (CGRP). These mediators co-activate resident antigen presenting cells and recruit additional immune system cells to the site of injury. T cells and macrophages then secrete additional inflammatory cytokines (tumor necrosis factor alpha (TNFα) and Interleukin 1 (IL1)) that changes the function of peripheral nociceptors via protein kinase cascades. Mechanistically, this is largely prompted by the changes in ion channel function (through phosphorylation) and expression of new channels. These include specific ion channels such as voltage gated sodium channels (Nav1.7–1.9) and non-specific cation channels (transient receptor potential cation channel subfamily V member 1 (TRPV1).

Fig. 2

Mechanisms of central sensitization that lead to ocular pain following a non-noxious stimulus (e.g., light or wind). After leaving the cornea, peripheral corneal nerves synapse with second-order neurons in the Vi/Vc and Vc/C1 regions within the trigeminal subnucleus caudalis. Sensory (touch) neurons also synapse with central neurons in this area. Increased peripheral traffic leads to the release of substance P (SP) and glutamate at the synapse junction. Several receptors respond to these mediators including the N-methyl-D-aspartate receptor (NMDAR) (ion channel that responds to glutamate), the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) (ion channel that responds to glutamate), and the neurokinin 1 receptor (NK1R) (G protein coupled receptor that responds to substance P). In a similar manner to what occurs in the periphery, the co-activation of these receptors leads to increased calcium (Ca2+) and phosphorylation of existing ion channels and production of more channels, leading to a more excitatory phenotype. Other mechanisms involved in central sensitization include decreased number and function of inhibitory interneurons (which results in pain amplification), activation of glial cells (with resulting central inflammation), and conversion of touch receptors into pain receptors. The latter has the effect of converting innocuous sensations to painful ones (hyperalgesia, allodynia). Of note, features of hyperalgesia and allodynia (in the form of sensitivity to wind and light) are often concomitant with dry eye symptoms.