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In the cornea, the nociceptors located in the most external layer provide a myriad of sensation modalities. Damage to these corneal nerve fibers can induce neuropathic pain. In response, corneal nerves become sensitized to previously non-noxious stimuli. Assessing corneal pain origin is a complex ophthalmic challenge due to variations in its causes and manifestations. Current FDA-approved therapies for corneal nociceptive pain, such as acetaminophen and NSAIDs, provide only broad-acting relief with unwanted side effects, highlighting the need for precision medicine for corneal nociceptive pain. A few targeted treatments, including perfluorohexyloctane (F6H8) eye drops and Optive Plus (TRPV1 antagonist), are FDA-approved, while others are in preclinical development. Treatments that target signaling pathways related to neurotrophic factors, such as nerve growth factors and ion channels, such as the transient receptor potential (TRP) family or tropomyosin receptor kinase A, may provide a potential combinatory therapeutic approach. This review describes the roles of nociceptors in corneal pain. In addition, it evaluates molecules within nociceptor signaling pathways for their potential to serve as targets for efficient therapeutic strategies for corneal nociceptive pain aimed at modulating neurotrophic factors and nociceptive channel sensitivity.<\/jats:p>","DOI":"10.3390\/ijms26104663","type":"journal-article","created":{"date-parts":[[2025,5,13]],"date-time":"2025-05-13T11:31:49Z","timestamp":1747135909000},"page":"4663","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Corneal Sensory Receptors and Pharmacological Therapies to Modulate Ocular Pain"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-0830-8441","authenticated-orcid":false,"given":"Ryan","family":"Park","sequence":"first","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, College of Medicine, University of Illinois Chicago, Chicago, IL 60612, 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University of Illinois Chicago, Chicago, IL 60612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-9202-8711","authenticated-orcid":false,"given":"Deneb","family":"Zavala","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, College of Medicine, University of Illinois Chicago, Chicago, IL 60612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tasha","family":"Merchant","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, College of Medicine, University of Illinois Chicago, Chicago, IL 60612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andres","family":"Gascon","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, College of Medicine, University of Illinois Chicago, Chicago, IL 60612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"Jung","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, College of Medicine, University of Illinois Chicago, Chicago, IL 60612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8027-7314","authenticated-orcid":false,"given":"Bianca","family":"Bigit","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, College of Medicine, University of Illinois Chicago, Chicago, IL 60612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dimitri T.","family":"Azar","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, College of Medicine, University of Illinois Chicago, Chicago, IL 60612, 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Clin. Investig."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Guerrero-Moreno, A., Baudouin, C., Parsadaniantz, S.M., and Goazigo, A.R.L. (2020). Morphological and Functional Changes of Corneal Nerves and Their Contribution to Peripheral and Central Sensory Abnormalities. Front. Cell. Neurosci., 14.","DOI":"10.3389\/fncel.2020.610342"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1097\/ICU.0000000000000578","article-title":"Corneal neurotization","volume":"30","author":"Koaik","year":"2019","journal-title":"Curr. Opin. Ophthalmol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.jtos.2016.09.004","article-title":"In Vivo Confocal Microscopy of Corneal Nerves in Health and Disease","volume":"15","author":"Cruzat","year":"2017","journal-title":"Ocul. Surf."},{"key":"ref_5","unstructured":"Belmonte, C., Tervo, T., and Gallar, J. (2024). Sensory Innervation of the Eye, US Elsevier Health."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Eguchi, H., Hiura, A., Nakagawa, H., Kusaka, S., and Shimomura, Y. (2017). Corneal Nerve Fiber Structure, Its Role in Corneal Function, and Its Changes in Corneal Diseases. BioMed Res. Int., 2017.","DOI":"10.1155\/2017\/3242649"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/j.survophthal.2013.09.002","article-title":"Corneal nerves in health and disease","volume":"59","author":"Shaheen","year":"2014","journal-title":"Surv. Ophthalmol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Fakih, D., Migeon, T., Moreau, N., Baudouin, C., R\u00e9aux-Le Goazigo, A., and M\u00e9lik Parsadaniantz, S. (2022). Transient Receptor Potential Channels: Important Players in Ocular Pain and Dry Eye Disease. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14091859"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1038\/nature02196","article-title":"TRP channels as cellular sensors","volume":"426","author":"Clapham","year":"2003","journal-title":"Nature"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jchemneu.2014.06.006","article-title":"Capsaicin-responsive corneal afferents do not contain TRPV1 at their central terminals in trigeminal nucleus caudalis in rats","volume":"61\u201362","author":"Hegarty","year":"2014","journal-title":"J. Chem. Neuroanat."},{"key":"ref_11","first-page":"392","article-title":"TRPV1, TRPA1, and TRPM8 are expressed in axon terminals in the cornea: TRPV1 axons contain CGRP and secretogranin II; TRPA1 axons contain secretogranin 3","volume":"26","author":"Schecterson","year":"2020","journal-title":"Mol. Vis."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Benitez-Angeles, M., Morales-Lazaro, S.L., Juarez-Gonzalez, E., and Rosenbaum, T. (2020). TRPV1: Structure, Endogenous Agonists, and Mechanisms. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21103421"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1016\/j.neuroscience.2005.12.020","article-title":"The role of the capsaicin receptor TRPV1 and acid-sensing ion channels (ASICS) in proton sensitivity of subpopulations of primary nociceptive neurons in rats and mice","volume":"139","author":"Leffler","year":"2006","journal-title":"Neuroscience"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1097\/01.j.pain.0000460335.49525.17","article-title":"Acid-sensing ion channels detect moderate acidifications to induce ocular pain","volume":"156","author":"Callejo","year":"2015","journal-title":"Pain"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Feng, X., Takayama, Y., Ohno, N., Kanda, H., Dai, Y., Sokabe, T., and Tominaga, M. (2020). Increased TRPV4 expression in non-myelinating Schwann cells is associated with demyelination after sciatic nerve injury. Commun. Biol., 3.","DOI":"10.1038\/s42003-020-01444-9"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"108257","DOI":"10.1016\/j.exer.2020.108257","article-title":"The role of TRPV4 channels in ocular function and pathologies","volume":"201","author":"Guarino","year":"2020","journal-title":"Exp. Eye Res."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Yamada, Y., Terada, Y., Yamanaka, R., Enoyoshi, M., and Ito, K. (2024). TRPV4 activation in human corneal epithelial cells promotes membrane mucin production. Biochem. Biophys. Res. Commun., 731.","DOI":"10.1016\/j.bbrc.2024.150402"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jtos.2024.12.002","article-title":"Neuropsin, TRPV4 and intracellular calcium mediate intrinsic photosensitivity in corneal epithelial cells","volume":"36","author":"Lapajne","year":"2025","journal-title":"Ocul. Surf."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"15502","DOI":"10.1073\/pnas.1312933110","article-title":"UVB radiation generates sunburn pain and affects skin by activating epidermal TRPV4 ion channels and triggering endothelin-1 signaling (vol 110, pg E3225, 2013)","volume":"110","author":"Moore","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Alamri, A.S., Wood, R.J., Ivanusic, J.J., and Brock, J.A. (2018). The neurochemistry and morphology of functionally identified corneal polymodal nociceptors and cold thermoreceptors. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0195108"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1016\/S0896-6273(04)00150-3","article-title":"Noxious cold ion channel TRPA1 is activated by pungent compounds and bradykinin","volume":"41","author":"Bandell","year":"2004","journal-title":"Neuron"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.conb.2019.11.006","article-title":"Regulation of pain by neuro-immune interactions between macrophages and nociceptor sensory neurons","volume":"62","author":"Chen","year":"2020","journal-title":"Curr. Opin. Neurobiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1007\/s00424-005-1427-1","article-title":"Multiple roles of calmodulin and other Ca2+-binding proteins in the functional regulation of TRP channels","volume":"451","author":"Zhu","year":"2005","journal-title":"Pflugers Arch."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.neulet.2009.03.082","article-title":"Down regulation of TRPC1 by shRNA reduces mechanosensitivity in mouse dorsal root ganglion neurons","volume":"457","author":"Staaf","year":"2009","journal-title":"Neurosci. Lett."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1152\/jn.00658.2011","article-title":"TRPC1 contributes to light-touch sensation and mechanical responses in low-threshold cutaneous sensory neurons","volume":"107","author":"Garrison","year":"2012","journal-title":"J. Neurophysiol."},{"key":"ref_26","first-page":"157","article-title":"Chapter Five\u2014Ion Channels in the Eye: Involvement in Ocular Pathologies","volume":"Volume 104","author":"Donev","year":"2016","journal-title":"Advances in Protein Chemistry and Structural Biology"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Comes, N., Gasull, X., and Callejo, G. (2021). Proton Sensing on the Ocular Surface: Implications in Eye Pain. Front. Pharmacol., 12.","DOI":"10.3389\/fphar.2021.773871"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"eaat9897","DOI":"10.1126\/scitranslmed.aat9897","article-title":"The mechanosensitive ion channel Piezo2 mediates sensitivity to mechanical pain in mice","volume":"10","author":"Murthy","year":"2018","journal-title":"Sci. Transl. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"eaat9892","DOI":"10.1126\/scitranslmed.aat9892","article-title":"PIEZO2 mediates injury-induced tactile pain in mice and humans","volume":"10","author":"Szczot","year":"2018","journal-title":"Sci. Transl. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"8976","DOI":"10.1523\/JNEUROSCI.0247-20.2020","article-title":"Piezo2 Mediates Low-Threshold Mechanically Evoked Pain in the Cornea","volume":"40","author":"Viana","year":"2020","journal-title":"J. Neurosci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e2416886122","DOI":"10.1073\/pnas.2416886122","article-title":"Nav1.8, an analgesic target for nonpsychotomimetic phytocannabinoids","volume":"122","author":"Ghovanloo","year":"2025","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1152\/jn.2001.86.2.629","article-title":"Contribution of Na 1.8 sodium channels to action potential electrogenesis in DRG neurons","volume":"86","author":"Renganathan","year":"2001","journal-title":"J. Neurophysiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"13373","DOI":"10.1073\/pnas.231376298","article-title":"Distinct potassium channels on pain-sensing neurons","volume":"98","author":"Rasband","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1331","DOI":"10.1016\/j.jmb.2008.11.048","article-title":"Molecular Biology of Background K Channels: Insights from K2P Knockout Mice","volume":"385","author":"Sabbadini","year":"2009","journal-title":"J. Mol. Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"6217","DOI":"10.1523\/JNEUROSCI.0893-09.2009","article-title":"TRPC1 and TRPC6 Channels Cooperate with TRPV4 to Mediate Mechanical Hyperalgesia and Nociceptor Sensitization","volume":"29","author":"Dina","year":"2009","journal-title":"J. Neurosci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"15167","DOI":"10.1074\/jbc.M110.106153","article-title":"Contribution of TRPV1-TRPA1 Interaction to the Single Channel Properties of the TRPA1 Channel","volume":"285","author":"Staruschenko","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1038\/nature719","article-title":"Identification of a cold receptor reveals a general role for TRP channels in thermosensation","volume":"416","author":"McKemy","year":"2002","journal-title":"Nature"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1016\/S0092-8674(03)00158-2","article-title":"ANKTM1, a TRP-like channel expressed in nociceptive neurons, is activated by cold temperatures","volume":"112","author":"Story","year":"2003","journal-title":"Cell"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1038\/nature02282","article-title":"Mustard oils and cannabinoids excite sensory nerve fibres through the TRP channel ANKTM1","volume":"427","author":"Jordt","year":"2004","journal-title":"Nature"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.neuroscience.2017.04.001","article-title":"Trpa1 Expression Levels and Excitability Brake by K Channels Influence Cold Sensitivity of Trpa1-Expressing Neurons","volume":"353","author":"Memon","year":"2017","journal-title":"Neuroscience"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1273","DOI":"10.1073\/pnas.0808487106","article-title":"TRPA1 acts as a cold sensor in vitro and in vivo","volume":"106","author":"Karashima","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"15165","DOI":"10.1523\/JNEUROSCI.2580-10.2010","article-title":"TRPA1 Contributes to Cold Hypersensitivity","volume":"30","author":"Murphy","year":"2010","journal-title":"J. Neurosci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1016\/j.ceca.2006.07.008","article-title":"Many cold sensitive peripheral neurons of the mouse do not express TRPM8 or TRPA1","volume":"41","author":"Munns","year":"2007","journal-title":"Cell Calcium"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1620\/tjem.2022.J004","article-title":"Age-Related Differences in Transient Receptor Potential Vanilloid 1 and 2 Expression Patterns in the Trigeminal Ganglion Neurons Contribute to Changes in the Palatal Mucosal Heat Pain Sensitivity","volume":"256","author":"Oto","year":"2022","journal-title":"Tohoku J. Exp. Med."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Frutos-Rinc\u00f3n, L., Luna, C., Aleixandre-Carrera, F., Velasco, E., Diaz-Tahoces, A., Meseguer, V., Gallar, J., and Acosta, M.C. (2023). The Contribution of TRPA1 to Corneal Thermosensitivity and Blink Regulation in Young and Aged Mice. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241612620"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1859","DOI":"10.1002\/cne.24454","article-title":"Morphological and functional changes in TRPM8-expressing corneal cold thermoreceptor neurons during aging and their impact on tearing in mice","volume":"526","author":"Alcalde","year":"2018","journal-title":"J. Comp. Neurol."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"M\u00e9ndez-Res\u00e9ndiz, K.A., Enciso-Pablo, O., Gonz\u00e1lez-Ram\u00edrez, R., Ju\u00e1rez-Contreras, R., Rosenbaum, T., and Morales-L\u00e1zaro, S.L. (2020). Steroids and TRP Channels: A Close Relationship. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21113819"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1111\/j.1471-4159.2011.07270.x","article-title":"Estrogen destabilizes microtubules through an ion-conductivity-independent TRPV1 pathway","volume":"117","author":"Goswami","year":"2011","journal-title":"J. Neurochem."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.jds.2021.06.007","article-title":"Review article Estrogen-dependent regulation of transient receptor potential vanilloid 1 (TRPV1) and P2X purinoceptor 3 (P2X3): Implication in burning mouth syndrome","volume":"17","author":"Seol","year":"2022","journal-title":"J. Dent. Sci."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"6304","DOI":"10.1038\/s41467-022-33835-3","article-title":"TRPM8 contributes to sex dimorphism by promoting recovery of normal sensitivity in a mouse model of chronic migraine","volume":"13","author":"Giorgi","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1016\/S0014-4835(03)00050-2","article-title":"Corneal nerves: Structure, contents and function","volume":"76","author":"Marfurt","year":"2003","journal-title":"Exp. Eye Res."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Yang, J.M., Wei, E.T., Kim, S.J., and Yoon, K.C. (2018). TRPM8 Channels and Dry Eye. Pharmaceuticals, 11.","DOI":"10.3390\/ph11040125"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"108243","DOI":"10.1016\/j.exer.2020.108243","article-title":"Corneal nerves anatomy, function, injury and regeneration","volume":"200","author":"Medeiros","year":"2020","journal-title":"Exp. Eye Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"59","DOI":"10.3109\/08820538.2015.1114853","article-title":"Understanding Neuropathic Corneal Pain\u2014Gaps and Current Therapeutic Approaches","volume":"31","author":"Goyal","year":"2016","journal-title":"Semin. Ophthalmol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1016\/j.exer.2003.09.023","article-title":"Neural basis of sensation in intact and injured corneas","volume":"78","author":"Belmonte","year":"2004","journal-title":"Exp. Eye Res."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1097\/IIO.0b013e31819242c9","article-title":"Corneal Nerve Alterations in Dry Eye-associated Ocular Surface Disease","volume":"49","author":"Dastjerdi","year":"2009","journal-title":"Int. Ophthalmol. Clin."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"3014","DOI":"10.12998\/wjcc.v10.i10.3014","article-title":"Changes in corneal nerve morphology and function in patients with dry eyes having type 2 diabetes","volume":"10","author":"Fang","year":"2022","journal-title":"World J. Clin. Cases"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"662","DOI":"10.1016\/j.ophtha.2014.11.006","article-title":"Effects of Corneal Nerve Density on the Response to Treatment in Dry Eye Disease","volume":"122","author":"Kheirkhah","year":"2015","journal-title":"Ophthalmology"},{"key":"ref_59","first-page":"1039","article-title":"Neuropathic corneal pain and dry eye: A continuum of nociception","volume":"106","author":"Dieckmann","year":"2021","journal-title":"Br. J. Ophthalmol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"5678","DOI":"10.1038\/s41467-019-13536-0","article-title":"TRPV1 activity and substance P release are required for corneal cold nociception","volume":"10","author":"Li","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"810","DOI":"10.1016\/j.ajpath.2024.01.015","article-title":"Transient Receptor Potential Vanilloid-1 Channels Facilitate Axonal Degeneration of Corneal Sensory Nerves in Dry Eye","volume":"194","author":"Pizzano","year":"2024","journal-title":"Am. J. Pathol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1178","DOI":"10.1126\/science.1957169","article-title":"Optical coherence tomography","volume":"254","author":"Huang","year":"1991","journal-title":"Science"},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Mikalauskiene, L., Grzybowski, A., and Zemaitiene, R. (2021). Ocular Surface Changes Associated with Ophthalmic Surgery. J. Clin. Med., 10.","DOI":"10.3390\/jcm10081642"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1105","DOI":"10.4103\/IJO.IJO_3406_22","article-title":"Refractive surgery and dry eye-An update","volume":"71","author":"Nair","year":"2023","journal-title":"Indian J. Ophthalmol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1006\/exer.1998.0469","article-title":"Recovery of Corneal Nerve Morphology Following Laser in situ Keratomileusis","volume":"66","author":"Linna","year":"1998","journal-title":"Exp. Eye Res."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1397","DOI":"10.1136\/bjo.2007.126821","article-title":"Corneal recovery after lasik for high myopia: A 2-year prospective confocal microscopic study","volume":"92","author":"Moilanen","year":"2008","journal-title":"Br. J. Ophthalmol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1059","DOI":"10.1016\/j.ajo.2005.07.027","article-title":"Recovery of Corneal Subbasal Nerve Density After PRK and LASIK","volume":"140","author":"Erie","year":"2005","journal-title":"Am. J. Ophthalmol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"159","DOI":"10.3928\/1081597X-20100224-01","article-title":"Structural-functional Correlations of Corneal Innervation After LASIK and Penetrating Keratoplasty","volume":"26","author":"Stachs","year":"2010","journal-title":"J. Refract. Surg."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"966","DOI":"10.1016\/j.jcrs.2019.02.019","article-title":"Long-term corneal subbasal nerve plexus regeneration after laser in situ keratomileusis","volume":"45","author":"Kozobolis","year":"2019","journal-title":"J. Cataract Refract. Surg."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1136\/bjo.2004.046888","article-title":"Corneal sensation after myopic and hyperopic LASIK: Clinical and confocal microscopic study","volume":"89","author":"Bragheeth","year":"2005","journal-title":"Br. J. Ophthalmol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1111\/opo.12723","article-title":"Alteration of the pattern of regenerative corneal subbasal nerves after laser in-situ keratomileusis surgery","volume":"40","author":"Chao","year":"2020","journal-title":"Ophthalmic Physiol. Opt."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1007\/s40123-021-00358-x","article-title":"Neuropathic Corneal Pain Following LASIK Surgery: A Retrospective Case Series","volume":"10","author":"Moshirfar","year":"2021","journal-title":"Ophthalmol. Ther."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1016\/j.ophtha.2014.10.004","article-title":"Dry Eye Disease after Refractive Surgery: Comparative Outcomes of Small Incision Lenticule Extraction versus LASIK","volume":"122","author":"Denoyer","year":"2015","journal-title":"Ophthalmology"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/S0002-9394(14)77412-4","article-title":"Corneal Sensitivity After Photorefractive Keratectomy","volume":"114","author":"Campos","year":"1992","journal-title":"Am. J. Ophthalmol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.ajo.2004.08.039","article-title":"Corneal barrier function, tear film stability, and corneal sensation after photorefractive keratectomy and laser in situ keratomileusis","volume":"139","author":"Nejima","year":"2005","journal-title":"Am. J. Ophthalmol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1064","DOI":"10.1167\/iovs.02-0247","article-title":"Long-Term Corneal Morphology after PRK by In Vivo Confocal Microscopy","volume":"44","author":"Moilanen","year":"2003","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1016\/j.survophthal.2012.11.004","article-title":"Management of post-photorefractive keratectomy pain","volume":"58","author":"Woreta","year":"2013","journal-title":"Surv. Ophthalmol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.1016\/j.ophtha.2009.01.001","article-title":"A Prospective, Contralateral Eye Study Comparing Thin-Flap LASIK (Sub-Bowman Keratomileusis) with Photorefractive Keratectomy","volume":"116","author":"Slade","year":"2009","journal-title":"Ophthalmology"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1097\/AJP.0000000000000271","article-title":"Mechanisms of Corneal Pain and Implications for Postoperative Pain After Laser Correction of Refractive Errors","volume":"32","author":"Garcia","year":"2016","journal-title":"Clin. J. Pain"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"4033","DOI":"10.1167\/iovs.07-0012","article-title":"Impulse activity in corneal sensory nerve fibers after photorefractive keratectomy","volume":"48","author":"Gallar","year":"2007","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1097\/ICO.0000000000002312","article-title":"Short-Term Impact of FS-LASIK and SMILE on Dry Eye Metrics and Corneal Nerve Morphology","volume":"39","author":"Recchioni","year":"2020","journal-title":"Cornea"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1040","DOI":"10.1097\/OPX.0b013e31829d9926","article-title":"Corneal Sensation After Corneal Refractive Surgery with Small Incision Lenticule Extraction","volume":"90","author":"Demirok","year":"2013","journal-title":"Optom. Vis. Sci."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1202","DOI":"10.3109\/02713683.2015.1107590","article-title":"Comparison of Corneal Biological Healing After Femtosecond LASIK and Small Incision Lenticule Extraction Procedure","volume":"41","author":"Xia","year":"2016","journal-title":"Curr. Eye Res."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.jtos.2013.09.001","article-title":"The Role of Corneal Innervation in LASIK-Induced Neuropathic Dry Eye","volume":"12","author":"Chao","year":"2014","journal-title":"Ocul. Surf."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/j.preteyeres.2018.11.005","article-title":"Corneal pain and experimental model development","volume":"71","author":"McKay","year":"2019","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"2200","DOI":"10.1016\/j.ophtha.2015.06.047","article-title":"Degeneration and Regeneration of Subbasal Corneal Nerves after Infectious Keratitis: A Longitudinal In Vivo Confocal Microscopy Study","volume":"122","author":"Abedi","year":"2015","journal-title":"Ophthalmology"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1002\/jcp.25623","article-title":"Understanding the Pathogenesis of Neurotrophic Keratitis: The Role of Corneal Nerves","volume":"232","author":"Mastropasqua","year":"2017","journal-title":"J. Cell. Physiol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1547","DOI":"10.1001\/jamaophthalmol.2013.5064","article-title":"Corneal Changes in Neurosurgically Induced Neurotrophic Keratitis","volume":"131","author":"Lambiase","year":"2013","journal-title":"JAMA Ophthalmol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"3403","DOI":"10.1167\/iovs.13-13774","article-title":"Corneal Sensory Nerve Activity in an Experimental Model of UV Keratitis","volume":"55","author":"Acosta","year":"2014","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1220","DOI":"10.4103\/1673-5374.213534","article-title":"Neurotrophic factors and corneal nerve regeneration","volume":"12","author":"Sacchetti","year":"2017","journal-title":"Neural Regen. Res."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1080\/02713683.2019.1675175","article-title":"Corneal Cells: Fine-tuning Nerve Regeneration","volume":"45","author":"Kowtharapu","year":"2020","journal-title":"Curr. Eye Res."},{"key":"ref_92","first-page":"1173","article-title":"Nerve regeneration by human corneal stromal keratocytes (CSKs) and stromal fibroblasts (SFs)","volume":"58","author":"Yam","year":"2017","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"100033","DOI":"10.1194\/jlr.TR120000954","article-title":"Docosanoid signaling modulates corneal nerve regeneration: Effect on tear secretion, wound healing, and neuropathic pain","volume":"62","author":"Pham","year":"2021","journal-title":"J. Lipid Res."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1167\/iovs.62.9.6","article-title":"Distribution of Corneal TRPV1 and Its Association With Immune Cells During Homeostasis and Injury","volume":"62","author":"Jiao","year":"2021","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"867","DOI":"10.1038\/s41385-022-00533-8","article-title":"TRPV1+ sensory nerves modulate corneal inflammation after epithelial abrasion via RAMP1 and SSTR5 signaling","volume":"15","author":"Liu","year":"2022","journal-title":"Mucosal Immunol."},{"key":"ref_96","doi-asserted-by":"crossref","unstructured":"Liedtke, W.B., and Heller, S. (2007). TRP Channels and Axon Pathfinding. TRP Ion Channel Function in Sensory Transduction and Cellular Signaling Cascades, CRC Press\/Taylor & Francis.","DOI":"10.1201\/9781420005844"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"894","DOI":"10.1038\/nature03477","article-title":"Essential role of TRPC channels in the guidance of nerve growth cones by brain-derived neurotrophic factor","volume":"434","author":"Li","year":"2005","journal-title":"Nature"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"898","DOI":"10.1038\/nature03478","article-title":"Requirement of TRPC channels in netrin-1-induced chemotropic turning of nerve growth cones","volume":"434","author":"Wang","year":"2005","journal-title":"Nature"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1038\/nn1459","article-title":"XTRPC1-dependent chemotropic guidance of neuronal growth cones","volume":"8","author":"Shim","year":"2005","journal-title":"Nat. Neurosci."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/j.it.2016.10.001","article-title":"Nociceptor Sensory Neuron\u2013Immune Interactions in Pain and Inflammation","volume":"38","author":"Verri","year":"2017","journal-title":"Trends Immunol."},{"key":"ref_101","doi-asserted-by":"crossref","unstructured":"Shinoda, M., Kubo, A., Hayashi, Y., and Iwata, K. (2019). Peripheral and Central Mechanisms of Persistent Orofacial Pain. Front. Neurosci., 13.","DOI":"10.3389\/fnins.2019.01227"},{"key":"ref_102","doi-asserted-by":"crossref","unstructured":"Ye, Y., Salvo, E., Romero-Reyes, M., Akerman, S., Shimizu, E., Kobayashi, Y., Michot, B., and Gibbs, J. (2021). Glia and Orofacial Pain: Progress and Future Directions. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22105345"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"5072","DOI":"10.1523\/JNEUROSCI.4476-07.2008","article-title":"Endogenous tumor necrosis factor alpha (TNFalpha) requires TNF receptor type 2 to generate heat hyperalgesia in a mouse cancer model","volume":"28","author":"Constantin","year":"2008","journal-title":"J. Neurosci."},{"key":"ref_104","doi-asserted-by":"crossref","unstructured":"Puri, S., Kenyon, B.M., and Hamrah, P. (2022). Immunomodulatory Role of Neuropeptides in the Cornea. Biomedicines, 10.","DOI":"10.3390\/biomedicines10081985"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/S0304-3959(98)00164-X","article-title":"Effect of NGF and anti-NGF on neuropathic pain in rats following chronic constriction injury of the sciatic nerve","volume":"79","author":"Ro","year":"1999","journal-title":"Pain"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"8593","DOI":"10.1523\/JNEUROSCI.3993-14.2015","article-title":"Persistent Nociception Triggered by Nerve Growth Factor (NGF) Is Mediated by TRPV1 and Oxidative Mechanisms","volume":"35","author":"Eskander","year":"2015","journal-title":"J. Neurosci."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/S0896-6273(02)00908-X","article-title":"p38 MAPK activation by NGF in primary sensory neurons after inflammation increases TRPV1 levels and maintains heat hyperalgesia","volume":"36","author":"Ji","year":"2002","journal-title":"Neuron"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1038\/sj.bjp.0701148","article-title":"Cytokines, nerve growth factor and inflammatory hyperalgesia: The contribution of tumour necrosis factor \u03b1","volume":"121","author":"Woolf","year":"1997","journal-title":"Br. J. Pharmacol."},{"key":"ref_109","doi-asserted-by":"crossref","unstructured":"Fortingo, N., Melnyk, S., Sutton, S.H., Watsky, M.A., and Bollag, W.B. (2022). Innate Immune System Activation, Inflammation and Corneal Wound Healing. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232314933"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"1778","DOI":"10.1038\/s41467-017-01841-5","article-title":"Exosomal cargo including microRNA regulates sensory neuron to macrophage communication after nerve trauma","volume":"8","author":"Simeoli","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_111","doi-asserted-by":"crossref","unstructured":"Strickland, I.T., Richards, L., Holmes, F.E., Wynick, D., Uney, J.B., and Wong, L.-F. (2011). Axotomy-Induced miR-21 Promotes Axon Growth in Adult Dorsal Root Ganglion Neurons. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0023423"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1515\/sjpain-2019-0138","article-title":"Role of the immune system in neuropathic pain","volume":"20","author":"Malcangio","year":"2019","journal-title":"Scand. J. Pain"},{"key":"ref_113","doi-asserted-by":"crossref","unstructured":"Dong, C.L., and Ubogu, E.E. (2022). Pro-inflammatory cytokines and leukocyte integrins associated with chronic neuropathic pain in traumatic and inflammatory neuropathies: Initial observations and hypotheses. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.935306"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"1361","DOI":"10.1038\/nn1992","article-title":"The neuropathic pain triad: Neurons, immune cells and glia","volume":"10","author":"Scholz","year":"2007","journal-title":"Nat. Neurosci."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"101105","DOI":"10.1016\/j.preteyeres.2022.101105","article-title":"Neuroimmune crosstalk in the cornea: The role of immune cells in corneal nerve maintenance during homeostasis and inflammation","volume":"91","author":"Wu","year":"2022","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"1106","DOI":"10.1016\/j.ajpath.2010.12.001","article-title":"IL-17 and VEGF are necessary for efficient corneal nerveregeneration","volume":"178","author":"Li","year":"2011","journal-title":"Am. J. Pathol."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.brainres.2006.02.035","article-title":"Peripheral and central distribution of TRPV1, substance P and CGRP of rat corneal neurons","volume":"1085","author":"Murata","year":"2006","journal-title":"Brain Res."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.jneuroim.2008.04.011","article-title":"Glia in pathological pain: A role for fractalkine","volume":"198","author":"Milligan","year":"2008","journal-title":"J. Neuroimmunol."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"4132","DOI":"10.1111\/febs.15846","article-title":"Senso-immunology: Crosstalk between nociceptive and immune systems","volume":"289","author":"Maruyama","year":"2022","journal-title":"Febs J."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1016\/j.jtos.2023.09.004","article-title":"Topical formulations of Aprepitant are safe and effective in relieving pain and inflammation, and drive neural regeneration","volume":"30","author":"Bonelli","year":"2023","journal-title":"Ocul. Surf."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1080\/00325481.2021.1949199","article-title":"Treating osteoarthritis pain: Mechanisms of action of acetaminophen, nonsteroidal anti-inflammatory drugs, opioids, and nerve growth factor antibodies","volume":"133","author":"Mantyh","year":"2021","journal-title":"Postgrad. Med."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"eabj9837","DOI":"10.1126\/scitranslmed.abj9837","article-title":"Developing nociceptor-selective treatments for acute and chronic pain","volume":"13","author":"Jayakar","year":"2021","journal-title":"Sci. Transl. Med."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"1142","DOI":"10.4103\/IJO.IJO_2778_22","article-title":"Contact lenses in dry eye disease and associated ocular surface disorders","volume":"71","author":"Chaudhary","year":"2023","journal-title":"Indian J. Ophthalmol."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1007\/s40135-017-0152-1","article-title":"Diagnosis and Treatment of Ocular Pain: The Ophthalmologist\u2019s Perspective","volume":"5","author":"Jacobs","year":"2017","journal-title":"Curr. Ophthalmol. Rep."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"102431","DOI":"10.1016\/j.coph.2024.102431","article-title":"Novel treatments for dry eye syndrome","volume":"75","author":"Roucaute","year":"2024","journal-title":"Curr. Opin. Pharmacol."},{"key":"ref_126","doi-asserted-by":"crossref","unstructured":"Delicado-Miralles, M., Velasco, E., D\u00edaz-Tahoces, A., Gallar, J., Acosta, M.C., and Aracil-Marco, A. (2021). Deciphering the Action of Perfluorohexyloctane Eye Drops to Reduce Ocular Discomfort and Pain. Front. Med., 8.","DOI":"10.3389\/fmed.2021.709712"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"1100","DOI":"10.1097\/ICO.0000000000003418","article-title":"Long-Term Safety and Efficacy of Perfluorohexyloctane Ophthalmic Solution for the Treatment of Patients With Dry Eye Disease: The KALAHARI Study","volume":"43","author":"Protzko","year":"2023","journal-title":"Cornea"},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"5503","DOI":"10.1167\/iovs.14-16247","article-title":"Protective Effects of L-Carnitine Against Oxidative Injury by Hyperosmolarity in Human Corneal Epithelial Cells","volume":"56","author":"Hua","year":"2015","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.2147\/OPTH.S58464","article-title":"A prospective, multicenter, noninterventional study of Optive Plus&reg; in the treatment of patients with dry eye: The prolipid study","volume":"8","author":"Kaercher","year":"2014","journal-title":"Clin. Ophthalmol."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1167\/tvst.12.9.5","article-title":"Ocular Pharmacology and Toxicology of TRPV1 Antagonist SAF312 (Libvatrep). Trans","volume":"12","author":"Mogi","year":"2023","journal-title":"Vis. Sci. Technol."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"1744806918777614","DOI":"10.1177\/1744806918777614","article-title":"Attenuation of TRPV1 by AMG-517 after nerve injury promotes peripheral axonal regeneration in rats","volume":"14","author":"Bai","year":"2018","journal-title":"Mol. Pain"},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1186\/s12974-021-02162-7","article-title":"Capsazepine decreases corneal pain syndrome in severe dry eye disease","volume":"18","author":"Fakih","year":"2021","journal-title":"J. Neuroinflamm."},{"key":"ref_133","doi-asserted-by":"crossref","unstructured":"Yang, M., Jung, S., Sethi, G., and Ahn, K. (2019). Pleiotropic Pharmacological Actions of Capsazepine, a Synthetic Analogue of Capsaicin, against Various Cancers and Inflammatory Diseases. Molecules, 24.","DOI":"10.3390\/molecules24050995"},{"key":"ref_134","doi-asserted-by":"crossref","unstructured":"Ang, S.-F., Moochhala, S.M., MacAry, P.A., and Bhatia, M. (2011). Hydrogen Sulfide and Neurogenic Inflammation in Polymicrobial Sepsis: Involvement of Substance P and ERK-NF-\u03baB Signaling. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0024535"},{"key":"ref_135","doi-asserted-by":"crossref","unstructured":"Lucius, A., Chhatwal, S., Valtink, M., Reinach, P.S., Li, A., Pleyer, U., and Mergler, S. (2023). L-Carnitine Suppresses Transient Receptor Potential Vanilloid Type 1 Activation in Human Corneal Epithelial Cells. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241411815"},{"key":"ref_136","doi-asserted-by":"crossref","unstructured":"Fakih, D., Baudouin, C., R\u00e9aux-Le Goazigo, A., and M\u00e9lik Parsadaniantz, S. (2020). TRPM8: A Therapeutic Target for Neuroinflammatory Symptoms Induced by Severe Dry Eye Disease. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21228756"},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"4556","DOI":"10.1167\/iovs.11-9054","article-title":"Evaluations of Tear Protein Markers in Dry Eye Disease: Repeatability of Measurement and Correlation with Disease","volume":"53","author":"Huang","year":"2012","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"1691","DOI":"10.1111\/bph.14177","article-title":"Antinociceptive effect of two novel transient receptor potential melastatin 8 antagonists in acute and chronic pain models in rat","volume":"175","author":"Russo","year":"2018","journal-title":"Br. J. Pharmacol."},{"key":"ref_139","doi-asserted-by":"crossref","unstructured":"Yoon, H.J., Kim, J., Yang, J.M., Wei, E.T., Kim, S.J., and Yoon, K.C. (2021). Topical TRPM8 Agonist for Relieving Neuropathic Ocular Pain in Patients with Dry Eye: A Pilot Study. J. Clin. Med., 10.","DOI":"10.3390\/jcm10020250"},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"1900","DOI":"10.1016\/j.bbamcr.2017.07.019","article-title":"Critical role of TRPC1 in thyroid hormone-dependent dopaminergic neuron development","volume":"1864","author":"Chen","year":"2017","journal-title":"Biochim. Biophys. Acta-Mol. Cell Res."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"1347","DOI":"10.1016\/S0161-6420(00)00163-9","article-title":"Topical treatment with nerve growth factor for neurotrophic keratitis","volume":"107","author":"Bonini","year":"2000","journal-title":"Ophthalmology"},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"5920","DOI":"10.1167\/iovs.13-12237","article-title":"CD11b+GR1+Myeloid Cells Secrete NGF and Promote Trigeminal Ganglion Neurite Growth: Implications for Corneal Nerve Regeneration","volume":"54","author":"Sarkar","year":"2013","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1016\/bs.ircmb.2014.10.002","article-title":"Biogenesis and Function of the NGF\/TrkA Signaling Endosome","volume":"314","author":"Marlin","year":"2015","journal-title":"Int. Rev. Cell Mol. Biol."},{"key":"ref_144","doi-asserted-by":"crossref","unstructured":"Liu, D., Li, X., Zhang, L., Hu, B., Hu, S., Zhang, X., and Hu, J. (2023). Small molecule inhibitors of osteoarthritis: Current development and future perspective. Front. Physiol., 14.","DOI":"10.3389\/fphys.2023.1156913"},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"1124","DOI":"10.1111\/j.1471-4159.2008.05698.x","article-title":"Human ProNGF: Biological effects and binding profiles at TrkA, P75 and sortilin","volume":"107","author":"Clewes","year":"2008","journal-title":"J. Neurochem."},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1038\/nature02319","article-title":"Sortilin is essential for proNGF-induced neuronal cell death","volume":"427","author":"Nykjaer","year":"2004","journal-title":"Nature"},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"1599","DOI":"10.1016\/j.joca.2019.05.028","article-title":"Efficacy and safety of intra-articular injection of tropomyosin receptor kinase A inhibitor in painful knee osteoarthritis: A randomized, double-blind and placebo-controlled study","volume":"27","author":"Krupka","year":"2019","journal-title":"Osteoarthr. Cartil."},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"1223","DOI":"10.2147\/JPR.S247472","article-title":"Nerve Growth Factor Signaling and Its Contribution to Pain","volume":"13","author":"Barker","year":"2020","journal-title":"J. Pain Res."},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"1590","DOI":"10.1016\/j.joca.2019.05.029","article-title":"Tropomyosin-related kinase A (TrkA) inhibition for the treatment of painful knee osteoarthritis: Results from a randomized controlled phase 2a trial","volume":"27","author":"Watt","year":"2019","journal-title":"Osteoarthr. Cartil."},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"e25285","DOI":"10.1002\/jnr.25285","article-title":"Neurophysiology of corneal neuropathic pain and emerging pharmacotherapeutics","volume":"102","author":"Asiedu","year":"2024","journal-title":"J. Neurosci. Res."},{"key":"ref_151","doi-asserted-by":"crossref","unstructured":"Joubert, F., Guerrero-Moreno, A., Fakih, D., Reboussin, E., Gaveriaux-Ruff, C., Acosta, M.C., Gallar, J., Sahel, J.A., Bodineau, L., and Baudouin, C. (2020). Topical treatment with a mu opioid receptor agonist alleviates corneal allodynia and corneal nerve sensitization in mice. Biomed. Pharmacother., 132.","DOI":"10.1016\/j.biopha.2020.110794"},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1056\/NEJMc1708349","article-title":"Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome REPLY","volume":"377","author":"Devinsky","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.archoralbio.2019.05.028","article-title":"Cannabidiol, cannabinol and their combinations act as peripheral analgesics in a rat model of myofascial pain","volume":"104","author":"Wong","year":"2019","journal-title":"Arch. Oral Biol."},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"3613","DOI":"10.1038\/s41467-023-39307-6","article-title":"Cannabidiol inhibits Nav channels through two distinct binding sites","volume":"14","author":"Huang","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_155","doi-asserted-by":"crossref","unstructured":"Ghovanloo, M.R., Dib-Hajj, S.D., Goodchild, S.J., Ruben, P.C., and Waxman, S.G. (2022). Non-psychotropic phytocannabinoid interactions with voltage-gated sodium channels: An update on cannabidiol and cannabigerol. Front. Physiol., 13.","DOI":"10.3389\/fphys.2022.1066455"},{"key":"ref_156","doi-asserted-by":"crossref","unstructured":"Garcia-Lopez, C., Gomez-Huertas, C., Sanchez-Gonzalez, J.M., Borroni, D., Rodriguez-Calvo-de-Mora, M., Romano, V., Rachwani-Anil, R., Ramos-Lopez, J.F., Ortiz-Perez, S., and Rocha-de-Lossada, C. (2022). Opioids and Ocular Surface Pathology: A Literature Review of New Treatments Horizons. J. Clin. Med., 11.","DOI":"10.3390\/jcm11051424"},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"4861491","DOI":"10.1155\/2018\/4861491","article-title":"Pirt Together with TRPV1 Is Involved in the Regulation of Neuropathic Pain","volume":"2018","author":"Wang","year":"2018","journal-title":"Neural Plast."},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"ENEURO.0168-19.2019","DOI":"10.1523\/ENEURO.0168-19.2019","article-title":"Nociceptor Deletion of Tsc2 Enhances Axon Regeneration by Inducing a Conditioning Injury Response in Dorsal Root Ganglia","volume":"6","author":"Carlin","year":"2019","journal-title":"Eneuro"},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"108428","DOI":"10.1016\/j.exer.2020.108428","article-title":"The effect of nerve growth factor on corneal nerve regeneration and dry eye after LASIK","volume":"203","author":"Gong","year":"2021","journal-title":"Exp. Eye Res."},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1186\/s13023-022-02237-5","article-title":"Eight months follow-up of corneal nerves and sensitivity after treatment with cenegermin for neurotrophic keratopathy","volume":"17","author":"Pedrotti","year":"2022","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_161","doi-asserted-by":"crossref","unstructured":"Verkest, C., Salinas, M., Diochot, S., Deval, E., Lingueglia, E., and Baron, A. (2022). Mechanisms of Action of the Peptide Toxins Targeting Human and Rodent Acid-Sensing Ion Channels and Relevance to Their In Vivo Analgesic Effects. Toxins, 14.","DOI":"10.3390\/toxins14100709"},{"key":"ref_162","doi-asserted-by":"crossref","unstructured":"Kung, C.-C., Huang, Y.-C., Hung, T.-Y., Teng, C.-Y., Lee, T.-Y., and Sun, W.-H. (2020). Deletion of Acid-Sensing Ion Channel 3 Relieves the Late Phase of Neuropathic Pain by Preventing Neuron Degeneration and Promoting Neuron Repair. Cells, 9.","DOI":"10.3390\/cells9112355"},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1016\/j.neuron.2018.03.023","article-title":"Peripheral and Central Mechanisms of Itch","volume":"98","author":"Dong","year":"2018","journal-title":"Neuron"},{"key":"ref_164","doi-asserted-by":"crossref","unstructured":"Nativi, C., Gualdani, R., Dragoni, E., Di Cesare Mannelli, L., Sostegni, S., Norcini, M., Gabrielli, G., la Marca, G., Richichi, B., and Francesconi, O. (2013). A TRPA1 antagonist reverts oxaliplatin-induced neuropathic pain. Sci. Rep., 3.","DOI":"10.1038\/srep02005"},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1093\/brain\/awac273","article-title":"TRPA1 modulation by Sigma-1 receptor prevents oxaliplatin-induced painful peripheral neuropathy","volume":"146","author":"Marcotti","year":"2023","journal-title":"Brain"},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"7020","DOI":"10.1038\/s41467-024-51181-4","article-title":"Phosphatidic acid is an endogenous negative regulator of PIEZO2 channels and mechanical sensitivity","volume":"15","author":"Gabrielle","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_167","doi-asserted-by":"crossref","unstructured":"Kim, G.-T., Siregar, A.S., Kim, E.-J., Lee, E.-S., Nyiramana, M.M., Woo, M.S., Hah, Y.-S., Han, J., and Kang, D. (2020). Upregulation of TRESK Channels Contributes to Motor and Sensory Recovery after Spinal Cord Injury. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21238997"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/10\/4663\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:32:03Z","timestamp":1760031123000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/10\/4663"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,13]]},"references-count":167,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2025,5]]}},"alternative-id":["ijms26104663"],"URL":"https:\/\/doi.org\/10.3390\/ijms26104663","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,13]]}}}