ArticlePain2016
Abnormal activity of corneal cold thermoreceptors underlies the unpleasant sensations in dry eye disease.
Article in Pain, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 65 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
65 citing papers in PubMed, 105 citations in OpenAlex.
- A double-blinded randomized clinical trial for pain perception: The efficacy and safety of topical cold saline solution anesthesia in phacoemulsification.Indian journal of ophthalmology · 2022Trial
- Detectability and Bias Indices of Pneumatic Corneal Stimuli Using Signal Detection Theory.Translational vision science & technology · 2020Trial
- Infraorbital Skin Application of Menthol Emulsion for Dry Eye Disease: A Randomized Clinical Trial.Ophthalmology and therapy · 2026Article
- Acute Tear Secretion Response to Menthol Delivered as a Vapor to the Eye: A Placebo-Controlled, Double-Blind, Randomized Clinical Trial.Pharmaceutics · 2026Article
- Corneal Innervation Research at a Crossroads: A Tool-Driven Roadmap for the Future.Investigative ophthalmology & visual science · 2026Review
- Validation and Comparative Analysis of a Contemporary Non-Contact Corneal Aesthesiometer.Journal of clinical medicine · 2026Article
- Modulation of corneal sensory processing and pain responses by dry eye and corneal wounding.Frontiers in cellular neuroscience · 2026Article
- Disproportionality analyses of acoltremon: a real-world safety assessment based on the the FDA adverse event reporting system database.Frontiers in medicine · 2026Article
- A narrative literature review about alpha-lipoic acid role in dry eye and ocular surface disease.Acta ophthalmologica · 2025Review
- CORONIS symposium 2023: Scientific and clinical frontiers in ocular surface innervation.Acta ophthalmologica · 2025Article
- Morphological aberration of corneal nerves in hyposecretory dry eye guinea pigs.Medical molecular morphology · 2025Article
- Non-contact confocal calcium imaging ofBiomedical optics express · 2025Article
- Tear deficiency transforms spatial distribution of corneal calcitonin gene-related peptide-positive nerves in rats.Frontiers in cellular neuroscience · 2025Article
- Effects of a Long-Acting Diquafosol Ophthalmic Solution on the Ocular Surface, Tolerability, and Usability in Dry Eye Disease.Advances in therapy · 2024Article
- Functional Changes of the Ocular Surface Sensory Nerves Due to Contact Lens Use in Young Symptomatic and Asymptomatic Users.Investigative ophthalmology & visual science · 2023Article
- Cyclosporine A Decreases Dryness-Induced Hyperexcitability of Corneal Cold-Sensitive Nerve Terminals.International journal of molecular sciences · 2023Article
- Autonomic Nerve Activity Features According to Dry Eye Type.Investigative ophthalmology & visual science · 2023Article
- Smartphone gaming induces dry eye symptoms and reduces blinking in school-aged children.Eye (London, England) · 2023Article
- Effect of TRPM8 Functional Loss on Corneal Epithelial Wound Healing in Mice.Investigative ophthalmology & visual science · 2023Article
- Benzalkonium chloride, a common ophthalmic preservative, compromises rat corneal cold sensitive nerve activity.The ocular surface · 2022Article
5 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
14 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Dry eye disease (DED) affects >10% of the population worldwide, and it provokes an unpleasant sensation of ocular dryness, whose underlying neural mechanisms remain unknown. Removal of the main lachrymal gland in guinea pigs caused long-term reduction of basal tearing accompanied by changes in the architecture and density of subbasal corneal nerves and epithelial terminals. After 4 weeks, ongoing impulse activity and responses to cooling of corneal cold thermoreceptor endings were enhanced. Menthol (200 μM) first excited and then inactivated this augmented spontaneous and cold-evoked activity. Comparatively, corneal polymodal nociceptors of tear-deficient eyes remained silent and exhibited only a mild sensitization to acidic stimulation, whereas mechanonociceptors were not affected. Dryness-induced changes in peripheral cold thermoreceptor responsiveness developed in parallel with a progressive excitability enhancement of corneal cold trigeminal ganglion neurons, primarily due to an increase of sodium currents and a decrease of potassium currents. In corneal polymodal nociceptor neurons, sodium currents were enhanced whereas potassium currents remain unaltered. In healthy humans, exposure of the eye surface to menthol vapors or to cold air currents evoked unpleasant sensations accompanied by increased blinking frequency that we attributed to cold thermoreceptor stimulation. Notably, stimulation with menthol reduced the ongoing background discomfort of patients with DED, conceivably due to use-dependent inactivation of cold thermoreceptors. Together, these data indicate that cold thermoreceptors contribute importantly to the detection and signaling of ocular surface wetness, and develop under chronic eye dryness conditions an injury-evoked neuropathic firing that seems to underlie the unpleasant sensations experienced by patients with DED.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.