Corneal Hypersensitivity Research Articles

Corneal hypersensitivity to cold stimuli in symptomatic computer users

Corneal hypersensitivity to cold stimuli in symptomatic computer users

Rethinking Sjögren Beyond Inflammation: Considering the Role of Nerves in Driving Disease Manifestations.

Sjögren syndrome (SS) is a chronic inflammatory autoimmune disease characterized by destruction of mucosal glands resulting in dry eye and dry mouth. Ocular presentations can be heterogenous in SS with corneal nerves abnormalities that are structural, functional, or both. Some individuals present with corneal hyposensitivity, with a phenotype of decreased tear production and epithelial disruption. Others present with corneal hypersensitivity, with a phenotype of neuropathic pain including light sensitivity and pain out of proportion to signs of tear dysfunction. A similar correlate can be found outside the eye, with dry mouth predominating in some individuals while pain conditions predominate in others. Understanding how nerve status affects SS phenotype is an important first step to improving disease management by targeting nerve abnormalities, as well as inflammation.

Alteration of neural activity and neuroinflammatory factors in the insular cortex of mice with corneal neuropathic pain

Dry eye disease (DED) affects nearly 55% of people worldwide; several studies have proposed that central sensitization and neuroinflammation may contribute to the developing corneal neuropathic pain of DED, while the underlying mechanisms of this contribution remain to be investigated. Excision of extra orbital lacrimal glands established the dry eye model. Corneal hypersensitivity was examined through chemical and mechanical stimulation, and open field test measured the anxiety levels. Restingstate fMRI is a method of functional magnetic resonance imaging (rs-fMRI) was performed for anatomical involvement of the brain regions. The amplitude of low-frequency fluctuation (ALFF) determined brain activity. Immunofluorescence testing and Quantitative real-time polymerase chain reaction were also performed to further validate the findings. Compared with the Sham group, ALFF signals in the supplemental somatosensory area, secondary auditory cortex, agranular insular cortex, temporal association areas, and ectorhinal cortex brain areas were increased in the dry eye group. This change of ALFF in the insular cortex was linked with the increment in corneal hypersensitivity (p < 0.01), c-Fos (p < 0.001), brain-derived neurotrophic factor (p < 0.01), TNF-α, IL-6, and IL-1β (p < 0.05). In contrast, IL-10 levels (p < 0.05) decreased in the dry eye group. DED-induced corneal hypersensitivity and upregulation of inflammatory cytokines could be blocked by insular cortex injection of Tyrosine Kinase receptor B agonist cyclotraxin-B (p < 0.01) without affecting anxiety levels. Our study reveals that the functional activity of the brain associated with corneal neuropathic pain and neuroinflammation in the insular cortex might contribute to dry eye-related corneal neuropathic pain.

Association between mask-associated dry eye (MADE) and corneal sensations

To determine the risk of mask-associated dry eye (MADE), we investigated the fluorescein tear break-up time (FBUT), ocular surface temperature and blood flow, along with corneal sensitivity, in mask wearers. We enrolled 60 mask wearers (mean age, 27.1 ± 5.2 years) and then measured FBUT, corneal temperature and conjunctival blood flow without wearing masks (no mask), with masks, and with taped masks. We defined MADE as the condition in which dry eye symptoms appeared and the FBUT with mask was less than 5 s. The FBUT with a mask was significantly shorter compared to the no mask and taped mask groups (P < 0.01 and P < 0.05). The corneal temperature difference and conjunctival blood flow difference were significantly higher after wearing a mask than after wearing a taped mask (P < 0.01). Of the 60 subjects, 13 were diagnosed with MADE. Pain sensitivity and the Ocular Surface Disease Index (P < 0.05 and P < 0.01) were significantly higher in the MADE group, with the FBUT without masks (P < 0.05) significantly shorter than in the non-MADE group. MADE may be associated with corneal hypersensitivity. Wearing masks decreased FBUT and increased ocular surface temperature and blood flow. Taping the top edge of masks prevented these changes. Fitting masks properly may reduce MADE risk.

Diquafosol sodium reduces neuronal activity in trigeminal subnucleus caudalis in a rat model of chronic dry eye disease

Patients with persistent and severe dry eye disease (DED) have corneal hypersensitivity, resulting in ocular pain, and diquafosol sodium, a potent P2Y2 receptor agonist, is commonly used to improve the resultant tear film stability. This study determined the effects of diquafosol instillation on the suppression of trigeminal subnucleus caudalis (Vc) neuronal activity and ocular pain by enhancing tear film stability in the model for chronic DED. The effects of diquafosol on the ocular surface were assessed by the topical application for 28 days, starting from the 14th day since unilateral exorbital gland removal (chronic DED). Loss of tear volume secretion in chronic DED rats was significantly reversed by diquafosol instillation after 28 days, compared with saline treatment. The number of eyeblinks and pERK-IR neurons in the superficial laminae of Vc following hypertonic saline administration to the ocular surface was lower in diquafosol-treated chronic DED rats than in saline-treated rats. The neuronal activity evoked by hypertonic saline and mechanical stimulation along with the spontaneous neuronal activity in the superficial laminae of the Vc were suppressed in diquafosol-treated chronic DED rats. These findings suggest that ocular surface instillation of diquafosol for 28 days attenuates the neuronal hyperactivity in the Vc and the ocular pain that often occurs in chronic DED.

Obstructive Sleep Apnea Affects Lacrimal Gland Function.

PurposeTo determine the effect of obstructive sleep apnea syndrome (OSA) on lacrimal gland function and its mechanism.MethodsMale mice aged seven to eight weeks were housed in cages with cyclic intermittent hypoxia to mimic OSA, and the control group was kept in a normal environment. Slit-lamp observation, fluorescein staining, and corneal sensitivity detection are used to assess cornea changes. Tear secretion was detected by phenol red cotton thread, and the pathological changes of lacrimal gland were observed by hematoxylin and eosin staining, oil red O staining, cholesterol and triglyceride kits, immunofluorescence staining, immunohistochemical staining, real-time polymerase chain reaction, transmission electron microscopy, and Western blot.ResultsStudies revealed a decreased tear secretion, corneal epithelial defects and corneal hypersensitivity. Myoepithelial cell damage, abnormal lipid accumulation, reduced cell proliferation, increased apoptosis and inflammatory cell infiltration in the lacrimal gland were also seen. Hifα and NF-κB signaling pathways, moreover, were activated, while Pparα was downregulated, in the lacrimal glands of OSA mice. Fenofibrate treatment significantly alleviated pathological changes of the lacrimal gland induced by OSA.ConclusionOSA disturbs the Hifα/Pparα/NF-κB signaling axis, which affects lacrimal gland structure and function and induces dry eye.

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

PurposePatients receiving chemotherapy may experience ocular discomfort and dry eye–like symptoms; the latter may be neuropathic in nature. This study assessed corneal and somatic hypersensitivity in male rats treated with paclitaxel and whether it was relieved by nicotinamide riboside (NR).MethodsCorneal sensitivity to tactile and chemical stimulation, basal tear production, and sensitivity of the hindpaw to tactile and cool stimuli were assessed before and after paclitaxel in the absence and presence of sustained treatment with 500 mg/kg per os NR. Corneal nerve density and hindpaw intraepidermal nerve fiber (IENF) density were also examined.ResultsPaclitaxel-treated rats developed corneal hypersensitivity to tactile stimuli, enhanced sensitivity to capsaicin but not hyperosmolar saline, and increased basal tear production. Corneal nerve density visualized with anti–β-tubulin or calcitonin gene-related peptide (CGRP) was unaffected. Paclitaxel induced tactile and cool hypersensitivity of the hindpaw and a loss of nonpeptidergic hindpaw IENFs visualized with anti-protein gene product (PGP) 9.5 and CGRP. NR reversed tactile hypersensitivity of the cornea without suppressing tear production or chemosensitivity; it did not alter corneal afferent density. NR also reversed tactile and cool hypersensitivity of the hindpaw without reversing the loss of hindpaw IENFs.ConclusionsThese findings suggest that paclitaxel may be a good translational model for chemotherapy-induced ocular discomfort and that NR may be useful for its relief. The ability of NR to relieve somatic tactile hypersensitivity independent of changes in sensory nerve innervation suggests that reversal of terminal arbor degeneration is not critical to the actions of NR.

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

The cornea is the most densely innervated and sensitive tissue in the body. The cornea is exclusively innervated by C- and A-delta fibers, including mechano-nociceptors that are triggered by noxious mechanical stimulation, polymodal nociceptors that are excited by mechanical, chemical, and thermal stimuli, and cold thermoreceptors that are activated by cooling. Noxious stimulations activate corneal nociceptors whose cell bodies are located in the trigeminal ganglion (TG) and project central axons to the trigeminal brainstem sensory complex. Ocular pain, in particular, that driven by corneal nerves, is considered to be a core symptom of inflammatory and traumatic disorders of the ocular surface. Ocular surface injury affecting corneal nerves and leading to inflammatory responses can occur under multiple pathological conditions, such as chemical burn, persistent dry eye, and corneal neuropathic pain as well as after some ophthalmological surgical interventions such as photorefractive surgery. This review depicts the morphological and functional changes of corneal nerve terminals following corneal damage and dry eye disease (DED), both ocular surface conditions leading to sensory abnormalities. In addition, the recent fundamental and clinical findings of the importance of peripheral and central neuroimmune interactions in the development of corneal hypersensitivity are discussed. Next, the cellular and molecular changes of corneal neurons in the TG and central structures that are driven by corneal nerve abnormalities are presented. A better understanding of the corneal nerve abnormalities as well as neuroimmune interactions may contribute to the identification of a novel therapeutic targets for alleviating corneal pain.

Topical treatment with a mu opioid receptor agonist alleviates corneal allodynia and corneal nerve sensitization in mice

Corneal pain is considered to be a core symptom of ocular surface disruption and inflammation. The management of this debilitating condition is still a therapeutic challenge. Recent evidence supports a role of the opioid system in the management of corneal nociception. However, the functional involvement of the mu opioid receptor (MOR) underlying this analgesic effect is not known. We first investigated the expression of the MOR in corneal nerve fibers and trigeminal ganglion (TG) neurons in control mice and a mouse model of corneal inflammatory pain. We then evaluated the anti-nociceptive and electrophysiological effects of DAMGO ([D-Ala2,N-Me-Phe4,Gly5-ol] enkephalin), a MOR-selective ligand. MOR immunoreactivity was detected in corneal nerve fibers and primary afferent neurons of the ophthalmic branch of the TG of naive mice. MOR expression was significantly higher in both structures under conditions of inflammatory corneal pain. Topical ocular administration of DAMGO strongly reduced both the mechanical (von Frey) and chemical (capsaicin) corneal hypersensitivity associated with inflammatory ocular pain. Repeated instillations of DAMGO also markedly reversed the elevated spontaneous activity of the ciliary nerve and responsiveness of corneal polymodal nociceptors that were observed in mice with corneal pain. Finally, these DAMGO-induced behavioral and electrophysiological responses were totally blunted by the topical application of naloxone methiodide, an opioid receptor antagonist. Overall, these results provide evidence that topical pharmacological MOR activation may constitute a therapeutic target for the treatment of corneal pain and improve corneal nerve function to alleviate chronic pain.

Chronic dry eye induced corneal hypersensitivity, neuroinflammatory responses, and synaptic plasticity in the mouse trigeminal brainstem

BackgroundDry eye disease (DED) is a multifactorial disease associated with ocular surface inflammation, pain, and nerve abnormalities. We studied the peripheral and central neuroinflammatory responses that occur during persistent DED using molecular, cellular, behavioral, and electrophysiological approaches.MethodsA mouse model of DED was obtained by unilateral excision of the extraorbital lachrymal gland (ELG) and Harderian gland (HG) of adult female C57BL/6 mice. In vivo tests were conducted at 7, 14, and 21 days (d) after surgery. Tear production was measured by a phenol red test and corneal alterations and inflammation were assessed by fluorescein staining and in vivo confocal microscopy. Corneal nerve morphology was evaluated by nerve staining. Mechanical corneal sensitivity was monitored using von Frey filaments. Multi-unit extracellular recording of ciliary nerve fiber activity was used to monitor spontaneous corneal nerve activity. RT-qPCR and immunostaining were used to determine RNA and protein levels at d21.ResultsWe observed a marked reduction of tear production and the development of corneal inflammation at d7, d14, and d21 post-surgery in DED animals. Chronic DE induced a reduction of intraepithelial corneal nerve terminals. Behavioral and electrophysiological studies showed that the DED animals developed time-dependent mechanical corneal hypersensitivity accompanied by increased spontaneous ciliary nerve fiber electrical activity. Consistent with these findings, DED mice exhibited central presynaptic plasticity, demonstrated by a higher Piccolo immunoreactivity in the ipsilateral trigeminal brainstem sensory complex (TBSC). At d21 post-surgery, mRNA levels of pro-inflammatory (IL-6 and IL-1β), astrocyte (GFAP), and oxidative (iNOS2 and NOX4) markers increased significantly in the ipsilateral trigeminal ganglion (TG). This correlated with an increase in Iba1, GFAP, and ATF3 immunostaining in the ipsilateral TG of DED animals. Furthermore, pro-inflammatory cytokines (IL-6, TNFα, IL-1β, and CCL2), iNOS2, neuronal (ATF3 and FOS), and microglial (CD68 and Itgam) markers were also upregulated in the TBSC of DED animals at d21, along with increased immunoreactivity against GFAP and Iba1.ConclusionsOverall, these data highlight peripheral sensitization and neuroinflammatory responses that participate in the development and maintenance of dry eye-related pain. This model may be useful to identify new analgesic molecules to alleviate ocular pain.

Upregulation of the mu‐opioid receptor in the cornea and trigeminal ganglion following corneal inflammatory pain

AbstractOcular pain following corneal injury is frequently observed in clinic, but its management remains as therapeutic challenge. The innervation of the cornea is provided by sensitive neurons located in the ophthalmic branch of trigeminal ganglion (TG). We recently reported that increasing endogenous enkephalin levels reduced ocular pain in a opioid receptor‐mediated manner (Reaux‐Le Goazigo et al., 2019). As the expression of the mu opioid receptor (MOR) in the cornea and TG is not known, this work aims to study MOR distribution both in control and under inflammatory pain conditions.MethodologyAdult male mice were submitted to a corneal scraping followed by 10 μL of lipopolysaccharide (LPS) at day 1 and day 3. Mechanical corneal sensitivity was measured by Von Frey filaments and corneal integrity was evaluated with in vivo confocal microscopy (IVCM). At D5, animals were perfused with 4% PFA to study the MOR expression by immunofluorescence (IF) and in situ hybridization (RNAscope method) in the ipsilateral cornea and TG. Images were captured with a confocal microscope and staining was quantified using imageJ.ResultsA corneal scraping and LPS instillation induced a mechanical corneal hypersensitivity compared to control mice. IVCM images showed a superficial epithelium alteration and inflammatory cells. IF experiments highlight the presence of MOR in corneal nerve fibers in both groups of animals but an increase of MOR immunoreactivity was noted in scraping + LPS mice. At the level of the ophthalmic branch of TG, MOR (protein and mRNA) was detected in a large population of primary sensory neurons. Quantification of MOR mRNA signal revealed a significant (+60%) increase of the receptor following corneal pain.ConclusionThis study provides novel information about the distribution of MOR in the cornea and TG in control and under corneal pain condition. Altogether, these results suggest that MOR could constitute a new therapeutic target for inflammatory ocular pain.

Randomized Controlled Study to Investigate the Effect of Topical Diquafosol Tetrasodium on Corneal Sensitivity in Short Tear Break-Up Time Dry Eye.

Complex mechanisms underlie dry eye (DE) symptom provocation. In particular, corneal hypersensitivity may provoke symptoms in short tear break-up time (BUT) DE characterized by tear film instability. We hypothesized that improved tear film stability may alleviate corneal sensitivity in patients with short tear BUT DE. Therefore, we investigated the effect of topical diquafosol tetrasodium (DQS) on corneal sensitivity in unstable tear film DE. This prospective, randomized study included 27 subjects (age: 39.1 ± 8.4years; range: 25-59years) with short tear BUT DE, defined based on the presence of DE symptoms and tear film instability. Subjects were randomly divided into DQS (3% DQS, 12 subjects) and artificial tear (AT; preservative-free AT, 15 subjects) groups. Subjects applied the medication 6 times a day for 5weeks. The perception of touch (S-touch) and pain (S-pain) sensitivity was measured using a Cochet-Bonnet esthesiometer. Tear evaluation, corneal sensitivity, and DE symptoms were compared before and after DQS or AT administration. The correlation between the improvement degrees of corneal sensitivity and DE symptoms following medication was analyzed. DQS significantly improved tear BUT and tear meniscus height (TMH) scores (p < 0.05), while AT significantly improved tear BUT (p < 0.05) but not TMH score. Mean S-pain and DE symptom scores were lower after medication use in the DQS (S-pain and DE symptoms: p < 0.05) and AT groups (S-pain: p = 0.05; DE symptoms: p < 0.05). However, S-touch did not change significantly in either group. A positive correlation was observed between the improvement degrees of S-pain and DE symptoms in the overall subjects studied. Both DQS and AT alleviate corneal hypersensitivity and DE symptoms in eyes with short tear BUT DE. However, DQS seems to be more effective to adjust tear environment, leading to the normalization of corneal sensitivity and DE symptoms. UMIN Clinical Trials Registry Identifier, UMIN000014536.

Hypersensitivity Following Excimer Laser Ablation Through the Corneal Epithelium

From our preliminary study, we found corneal hypersensitivity after excimer laser. To study the effects of corneal epithelial wound healing on corneal sensitivity, we investigated the recovery of corneal sensitivity following excimer laser and manual epithelial debridement. The corneal epithelium of the right eye of New Zealand white rabbits (n = 19) was manually debrided and the left eye was ablated with the excimer laser (5 Hz, 160 mJ/cm2, 47-micrometer depth). The wound-healing rate was measured up to 46 hours. Corneal sensitivity was measured for 10 weeks. There was no significant difference in the wound-healing rate, but at 36 hours there was a reduction in wound-healing rate of the excimer ablated corneas. In the laser-ablated cornea, sensitivity rapidly increased to a normal level by day 5, and then it continued to increase gradually and reached a maximum at day 42. Thereafter, it retained a higher level than normal up to 10 weeks. There were significant differences in the recovery of sensitivity following excimer ablation and manual debridement. These results show the development of a lasting enhanced sensitivity in the cornea after excimer laser ablation, suggesting the need to conduct further studies of neural plasticity and sensory thresholds following interventions on the corneal surface.

Subconjunctival injection of antilymphocyte serum during corneal hypersensitivity to heterologous alubmin.

Thirty-two rabbits were immunized by subcutaneous human serum albumin in Freund's adjuvant and challenged after four weeks by intracorneal injection in both eyes. On a random and blind basis, one of the eyes in each animal received three consecutive injections of antilymphocyte serum obtained from rats and the other eye the same dose of normal rat serum. Statistical analysis of results showed no significant difference between both treatments. Two eyes treated with antilymphocyte serum had limbal necrosis with uveal prolapse.

Suppression of the Corneal Hypersensitivity Reaction

Suppression of the Corneal Hypersensitivity Reaction

Experimental disciform keratitis: I. Immune response of the cornea to herpes simplex virus

Large inocula of washed viable herpes simplex virus injected into the corneal stroma caused an acute inflammatory response in the cornea, conjunctiva, iris, and ciliary body. This reaction is due to an infection that reaches its peak in 7 days and subsides in 8 to 13 days. When virus was reinjected a month or more later, the majority of corneas did not suffer recurrence of inflammatory reactions. There to four corneal injections of virus given 2 to 5 weeks apart led to brief periods of corneal clouding which could also be clicited by noninfected chorioallantoic membrane (CAM) proteins. Only one cornea in 28 had a brief clouding response which could not be related to CAM protein. None of the corneal clouding reactions was permanent but cleared after 7 days and, apart from minor, trauma-induced scars, all corneas returned to full clarity. Corneas sensitized with heat-inactivated virus developed negative or very low titers of neutralizing antibody, but intracorneal or intra-aqueous injections of viable virus led to high titers of such antibody in corneal extracts as well as serum. A conclusion is drawn that corneal hypersensitivity to herpes simplex virus, for at lcast two widely divergent strains, could not be related to the clinical problem of disciform keratitis on an experimental basis.

Experimental production of graft reactions with suppression by topical corticosteroids.

The primary purpose of this study was to obtain a reliable experimental model of the immune corneal reaction, and then to study its modification or suppression by corticosteroids. Such a system might also serve as a quantitative method of drug assay. It was thought that a simple model which did not require prior vascularization or antigen injection would be most desirable. Graft rejection in penetrating homografts in rabbits requires preliminary treatment of host corneas to obtain extensive corneal vascularization, 1 or the ancillary use of skin grafts from the same donor to the host, usually two weeks postcorneal grafting. 2,3 Even in interlamellar heterografts, conjunctival incarceration into the corneal pocket in two areas has been suggested to help induce corneal neovascularization and accentuation of the graft rejection. 4 However, in no previous study has an effect of topical corticosteroids been demonstrated. Other systems to study corneal hypersensitivity have been used,

The limbal cellar infiltrate in experimental corneal hypersensitivity. I. Morphologic studies after primary sensitization.

The injection of soluble protein antigens into the normal cornea induces a biphasic allergic reaction. Previous studies suggest that the early phase reaction (characterized by corneal clouding and circumlimbal flare) is mediated by delayed (cellular) hypersensitivity, while the late phase response (Wessely ring) results from local antigen-antibody interaction. 1-3 Earlier histologic studies of this reaction indicate that the specific cellular elements responding to antigenic stimulation are not found in the cornea, even though the cornea is the site of the gross response. Instead, the immunologically activated cells appear aggregated circumferentially at the limbus. 1 Within this cellular infiltrate an orderly transformation has been described. Associated with the early phase response, cells which were predominantly of the lymphoidmononuclear series were noted, while the infiltrate accompanying the late phase response was predominantly plasmocytic in type. In the interval between the two phases, though the sensitized eye appeared clinically normal, cellular forms intermediate

Subconjunctival steroids and corneal hypersensitivity.

Much attention has been given to the clinical and pathological events which occur following the injection of antigenic substances into rabbit cornea. 1-6 Within five days following injection, conjunctival and limbal hyperemia develop, followed by diffuse corneal clouding. Histopathologically, the cornea shows edema and infiltration by lymphocytes and mononuclear cells. This tissue reaction has been shown to be a manifestation of delayed-type hypersensitivity according to the following criteria: the lack of circulating antibody, a delayed-type skin hypersensitivity to specific antigen, and the ability to passively transfer this tissue hypersensitivity only with whole lymphoid cells from the sensitized animal. The initial conjunctival inflammation and corneal clouding disappear within one week, leaving a clinically normal eye. Between 12 and 18 days after injection, however, marked local inflammatory signs return, accompanied by corneal neovascularization and corneal clouding; and, depending on the dose of antigen initially injected, a white ring (Wessely ring) appears in

Further studies on the suppression of corneal hypersensitivity by antimetabolites.

Studies of experimentally induced immune phenomena, as they occur in the cornea, have revealed that this avascular tissue is apparently able to support cellular-mediated as well as antibody-mediated hypersensitivity reactions. 1 The authors have previously shown that both types of immune response which follow sensitization of the cornea to a soluble protein antigen (bovine serum albumin [BSA] ) can be inhibited if the antimetabolite 6-mercaptopurine (6-MP) is administered concomitantly with the antigen. 2 The drug maintains the cornea in a transparent state and suppresses antibody production as well as the infiltration of the limbus by specific, immunologically competent cells. In the present study, the initiation of 6-MP therapy was varied with respect to the time of introduction of a foreign protein into the cornea. In this manner, the immunosuppressive efficacy of (1) Pretreatment, (2) short term administration of the drug, and (3) delayed initiation of therapy upon corneal hypersensitivity was investigated.