How does chronic dry eye shape peripheral and central nociceptive systems?

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.

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“…These cellular and molecular changes lead to pain and promote anxiety-like behaviors. Modified from Guerrero-Moreno et al (2021).…”

Section: Evidence That Corneal Nerve Abnormalities Shape the Central mentioning

confidence: 99%

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

Guerrero-Moreno

Baudouin

Mélik-Parsadaniantz

et al. 2020

Front. Cell. Neurosci.

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“…7A), synaptic function pathways (Table 2; Tables S14,18,22). In the cornea, miR-183C target genes identi ed in the SNS-CKO and miR-183C KO mice (Table S15,16, 19,20,23,24) are prominently enriched in regulation of synaptic functions, in addition to axonogenesis and axon projection (Tables 3 & 4). These data collectively suggest that miR-183C regulates sensory neuronal projection and synaptic function through directly targeting genes involved in these biological processes.…”

Section: Mir-183c Modulates the Functions Of Sensory Neurons And Myel...mentioning

confidence: 99%

“…The cornea is the most densely sensory-innerved tissue in the body [17][18][19] . Sensory innervation of the cornea not only provides bodily sensation to various stimuli but also plays important roles in the homeostasis of the cornea as well as the pathogenesis of corneal diseases through neuroimmune interactions [18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33] . microRNAs (miRNAs) are small, non-coding RNAs and are post-transcriptional regulators of gene expression [34][35][36][37] .…”

Section: Introductionmentioning

confidence: 99%

The miR-183/96/182 cluster regulates sensory innervation, resident myeloid cells and functions of the cornea through cell-type-specfic target genes

Gupta,

Somayajulu,

Gurdziel

et al. 2024

Preprint

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The conserved miR-183/96/182 cluster (miR-183C) is expressed in both corneal resident myeloid cells (CRMCs) and sensory nerves (CSN) and modulates corneal immune/inflammatory responses. To uncover cell type-specific roles of miR-183C in CRMC and CSN and their contribute to corneal physiology, myeloid-specific miR-183C conditional knockout (MS-CKO), and sensory nerve-specific CKO (SNS-CKO) mice were produced and characterized in comparison to the conventional miR-183C KO. Immunofluorescence and confocal microscopy of flatmount corneas, corneal sensitivity, and tear volume assays were performed in young adult naïve mice; 3’RNA sequencing (Seq) in the trigeminal ganglion (TG), cornea and CRMCs. Our results showed that, similar to conventional KO mice, the numbers of CRMCs were increased in both MS-CKO and SNS-CKO vs age- and sex-matched WT control littermates, suggesting intrinsic and extrinsic regulations of miR-183C on CRMCs. In the miR-183C KO and SNS-CKO, but not the MS-CKO mice, CSN density was decreased in the epithelial layer of the cornea, but not the stromal layer. Functionally, corneal sensitivity and basal tear volume were reduced in the KO and SNS-CKO, but not the MS-CKO mice. Tear volume in males is consistently higher than female WT mice. Bioinformatic analyses of the transcriptomes revealed a series of cell-type specific target genes of miR-183C in TG sensory neurons and CRMCs. Our data elucidate that miR-183C imposes intrinsic and extrinsic regulation on the establishment and function of CSN and CRMCs by cell-specific target genes. miR-183C modulates corneal sensitivity and tear production through its regulation of corneal sensory innervation.

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“…Dry eye disease (DED) is a multifactorial disorder of the ocular surface, estimated to affect up to 50% of the global population [1–10]. It is characterized by loss of tear film homeostasis and accompanied by tear film instability, ocular surface inflammation, and damage, hyperosmolarity, and neurosensory abnormalities [11–16,17 ▪▪ ,18]. Symptoms of DED include blurred vision, burning, tearing, foreign body sensation, and ocular fatigue, ranging in severity from transient discomfort to incapacitating pain and visual impairment [20–24].…”

Section: Introductionmentioning

confidence: 99%

Neurostimulation for dry eye disease

London

Pincovich

Solomon

2022

Current Opinion in Allergy &Amp; Clinical Immunology

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Purpose of reviewTo review the neuroanatomy and physiology of the basal and reflex tearing and present the available and developing therapies using the concept of neurostimulation in dry eye disease (DED). Recent findingsThe most prevalent current DED treatments seek to supplement low tear volume and tear components or reduce inflammation. Neurostimulation is a unique approach gaining momentum in recent years, geared toward increasing the production of all basal tear components by stimulating the nerves responsible for producing the various tear components. The neuroanatomy of the lacrimal unit provides several possible access points to stimulate tear production through two arms of the sensory trigeminal nerves. Modes of stimulation include chemical or energy in electrical or magnetic form. Research thus far has shown that neurostimulation can achieve lacrimal, goblet cell, and meibomian gland stimulation. Subjectively it improves symptoms of DED. Clinically, neurostimulation has improved the signs and symptoms of DED by increasing basal tear production and tear volume.

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How does chronic dry eye shape peripheral and central nociceptive systems?

Cited by 9 publications

References 12 publications

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

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

The miR-183/96/182 cluster regulates sensory innervation, resident myeloid cells and functions of the cornea through cell-type-specfic target genes

Neurostimulation for dry eye disease

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