{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T21:57:53Z","timestamp":1791928673881,"version":"4.3.4"},"reference-count":53,"publisher":"Association for Research in Vision and Ophthalmology (ARVO)","issue":"8","license":[{"start":{"date-parts":[[2018,7,25]],"date-time":"2018-07-25T00:00:00Z","timestamp":1532476800000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Invest. Ophthalmol. Vis. Sci."],"published-print":{"date-parts":[[2018,7,25]]},"DOI":"10.1167\/iovs.18-24304","type":"journal-article","created":{"date-parts":[[2018,7,26]],"date-time":"2018-07-26T03:32:28Z","timestamp":1532575948000},"page":"3739","source":"Crossref","is-referenced-by-count":80,"title":["TRPV1 and TRPM8 Channels and Nocifensive Behavior in a Rat Model for Dry Eye"],"prefix":"10.1167","volume":"59","author":[{"given":"David A.","family":"Bereiter","sequence":"first","affiliation":[{"name":"Department of Diagnostic and Biological Sciences, University of Minnesota School of Dentistry, Minneapolis, Minnesota, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mostafeezur","family":"Rahman","sequence":"additional","affiliation":[{"name":"Department of Diagnostic and Biological Sciences, University of Minnesota School of Dentistry, Minneapolis, Minnesota, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Randall","family":"Thompson","sequence":"additional","affiliation":[{"name":"Department of Diagnostic and Biological Sciences, University of Minnesota School of Dentistry, Minneapolis, Minnesota, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pannaporn","family":"Stephenson","sequence":"additional","affiliation":[{"name":"Department of Diagnostic and Biological Sciences, University of Minnesota School of Dentistry, Minneapolis, Minnesota, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroto","family":"Saito","sequence":"additional","affiliation":[{"name":"Department of Diagnostic and Biological Sciences, University of Minnesota School of Dentistry, Minneapolis, Minnesota, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"27","reference":[{"key":"i1552-5783-59-8-3739-b01","doi-asserted-by":"crossref","unstructured":"Begley CG, Chalmers RL, Mitchell GL, et al. Characterization of ocular surface symptoms from optometric practices in North America. Cornea. 2001; 20: 610\u2013618.","DOI":"10.1097\/00003226-200108000-00011"},{"key":"i1552-5783-59-8-3739-b02","doi-asserted-by":"crossref","unstructured":"Spierer O, Felix ER, McClellan AL, et al. Corneal mechanical thresholds negatively associate with dry eye and ocular pain symptoms. Invest Ophthalmol Vis Sci. 2016; 57: 617\u2013625.","DOI":"10.1167\/iovs.15-18133"},{"key":"i1552-5783-59-8-3739-b03","doi-asserted-by":"crossref","unstructured":"Kalangara JP, Galor A, Levitt RC, et al. Characteristics of ocular pain complaints in patients with idiopathic dry eye symptoms. Eye Contact Lens. 2017; 43: 192\u2013198.","DOI":"10.1097\/ICL.0000000000000249"},{"key":"i1552-5783-59-8-3739-b04","doi-asserted-by":"crossref","unstructured":"Gadaria-Rathod N, Lee KI, Asbell PA. Emerging drugs for the treatment of dry eye disease. Expert Opin Emerg Drugs. 2013; 18: 121\u2013136.","DOI":"10.1517\/14728214.2013.791676"},{"key":"i1552-5783-59-8-3739-b05","doi-asserted-by":"crossref","unstructured":"Messmer EM. The pathophysiology, diagnosis, and treatment of dry eye disease. Dtsch Arztebl Int. 2015; 112: 71\u201381; quiz 82.","DOI":"10.3238\/arztebl.2015.0071"},{"key":"i1552-5783-59-8-3739-b06","doi-asserted-by":"crossref","unstructured":"Galor A, Batawi H, Felix ER, et al. Incomplete response to artificial tears is associated with features of neuropathic ocular pain. Br J Ophthalmol. 2016; 100: 745\u2013749.","DOI":"10.1136\/bjophthalmol-2015-307094"},{"key":"i1552-5783-59-8-3739-b07","doi-asserted-by":"crossref","unstructured":"Goyal S, Hamrah P. Understanding neuropathic corneal pain-gaps and current therapeutic approaches. Semin Ophthalmol. 2016; 31: 59\u201370.","DOI":"10.3109\/08820538.2015.1114853"},{"key":"i1552-5783-59-8-3739-b08","doi-asserted-by":"crossref","unstructured":"Crane AM, Feuer W, Felix ER, et al. Evidence of central sensitisation in those with dry eye symptoms and neuropathic-like ocular pain complaints: incomplete response to topical anaesthesia and generalised heightened sensitivity to evoked pain. Br J Ophthalmol. 2017; 101: 1238\u20131243.","DOI":"10.1136\/bjophthalmol-2016-309658"},{"key":"i1552-5783-59-8-3739-b09","doi-asserted-by":"crossref","unstructured":"Meng ID, Kurose M. The role of corneal afferent neurons in regulating tears under normal and dry eye conditions. Exp Eye Res. 2013; 117: 79\u201387.","DOI":"10.1016\/j.exer.2013.08.011"},{"key":"i1552-5783-59-8-3739-b10","doi-asserted-by":"crossref","unstructured":"Belmonte C, Acosta MC, Merayo-Lloves J, Gallar J. What causes eye pain? Curr Ophthalmol Rep. 2015; 3: 111\u2013121.","DOI":"10.1007\/s40135-015-0073-9"},{"key":"i1552-5783-59-8-3739-b11","doi-asserted-by":"crossref","unstructured":"Calonge M, Enriquez-de-Salamanca A, Diebold Y, et al. Dry eye disease as an inflammatory disorder. Ocul Immunol Inflamm. 2010; 18: 244\u2013253.","DOI":"10.3109\/09273941003721926"},{"key":"i1552-5783-59-8-3739-b12","doi-asserted-by":"crossref","unstructured":"Bron AJ, Tomlinson A, Foulks GN, et al. Rethinking dry eye disease: a perspective on clinical implications. Ocul Surf. 2014; 12: S1\u2013S31.","DOI":"10.1016\/j.jtos.2014.02.002"},{"key":"i1552-5783-59-8-3739-b13","doi-asserted-by":"crossref","unstructured":"Wei Y, Asbell PA. The core mechanism of dry eye disease is inflammation. Eye Contact Lens. 2014; 40: 248\u2013256.","DOI":"10.1097\/ICL.0000000000000042"},{"key":"i1552-5783-59-8-3739-b14","doi-asserted-by":"crossref","unstructured":"Stevenson W, Chen Y, Lee SM, et al. Extraorbital lacrimal gland excision: a reproducible model of severe aqueous tear-deficient dry eye disease. Cornea. 2014; 33: 1336\u20131341.","DOI":"10.1097\/ICO.0000000000000264"},{"key":"i1552-5783-59-8-3739-b15","doi-asserted-by":"crossref","unstructured":"Meng ID, Barton ST, Mecum NE, Kurose M. Corneal sensitivity following lacrimal gland excision in the rat. Invest Ophthalmol Vis Sci. 2015; 56: 3347\u20133354.","DOI":"10.1167\/iovs.15-16717"},{"key":"i1552-5783-59-8-3739-b16","doi-asserted-by":"crossref","unstructured":"Joossen C, Lanckacker E, Zakaria N, et al. Optimization and validation of an existing, surgical and robust dry eye rat model for the evaluation of therapeutic compounds. Exp Eye Res. 2016; 146: 172\u2013178.","DOI":"10.1016\/j.exer.2016.03.006"},{"key":"i1552-5783-59-8-3739-b17","doi-asserted-by":"crossref","unstructured":"Rahman M, Okamoto K, Thompson R, Katagiri A, Bereiter DA. Sensitization of trigeminal brainstem pathways in a model for tear deficient dry eye. Pain. 2015; 156: 942\u2013950.","DOI":"10.1097\/j.pain.0000000000000135"},{"key":"i1552-5783-59-8-3739-b18","doi-asserted-by":"crossref","unstructured":"Sullivan BD, Crews LA, Messmer EM, et al. Correlations between commonly used objective signs and symptoms for the diagnosis of dry eye disease: clinical implications. Acta Ophthalmol. 2014; 92: 161\u2013166.","DOI":"10.1111\/aos.12012"},{"key":"i1552-5783-59-8-3739-b19","doi-asserted-by":"crossref","unstructured":"Price TJ, Patwardhan A, Akopian AN, Hargreaves KM, Flores CM. Modulation of trigeminal sensory neuron activity by the dual cannabinoid-vanilloid agonists anandamide, N-arachidonoyl-dopamine and arachidonyl-2-chloroethylamide. Br J Pharmacol. 2004; 141: 1118\u20131130.","DOI":"10.1038\/sj.bjp.0705711"},{"key":"i1552-5783-59-8-3739-b20","doi-asserted-by":"crossref","unstructured":"Farazifard R, Safarpour F, Sheibani V, Javan M. Eye-wiping test: a sensitive animal model for acute trigeminal pain studies. Brain Res Brain Res Protoc. 2005; 16: 44\u201349.","DOI":"10.1016\/j.brainresprot.2005.10.003"},{"key":"i1552-5783-59-8-3739-b21","doi-asserted-by":"crossref","unstructured":"Shimada SG, LaMotte RH. Behavioral differentiation between itch and pain in mouse. Pain. 2008; 139: 681\u2013687.","DOI":"10.1016\/j.pain.2008.08.002"},{"key":"i1552-5783-59-8-3739-b22","doi-asserted-by":"crossref","unstructured":"Liu H, Begley C, Chen M, et al. A link between tear instability and hyperosmolarity in dry eye. Invest Ophthalmol Vis Sci. 2009; 50: 3671\u20133679.","DOI":"10.1167\/iovs.08-2689"},{"key":"i1552-5783-59-8-3739-b23","doi-asserted-by":"crossref","unstructured":"Rahman M, Okamoto K, Thompson R, Bereiter DA. Trigeminal pathways for hypertonic saline- and light-evoked corneal reflexes. Neuroscience. 2014; 277: 716\u2013723.","DOI":"10.1016\/j.neuroscience.2014.07.052"},{"key":"i1552-5783-59-8-3739-b24","doi-asserted-by":"crossref","unstructured":"Chen X, Belmonte C, Rang HP. Capsaicin and carbon dioxide act by distinct mechanisms on sensory nerve terminals in the cat cornea. Pain. 1997; 70: 23\u201329.","DOI":"10.1016\/S0304-3959(96)03256-3"},{"key":"i1552-5783-59-8-3739-b25","doi-asserted-by":"crossref","unstructured":"Saloman JL, Chung MK, Ro JY. P2X(3) and TRPV1 functionally interact and mediate sensitization of trigeminal sensory neurons. Neuroscience. 2013; 232: 226\u2013238.","DOI":"10.1016\/j.neuroscience.2012.11.015"},{"key":"i1552-5783-59-8-3739-b26","doi-asserted-by":"crossref","unstructured":"Liu BY, Lin YJ, Lee HF, Ho CY, Ruan T, Kou YR. Menthol suppresses laryngeal C-fiber hypersensitivity to cigarette smoke in a rat model of gastroesophageal reflux disease: the role of TRPM8. J Appl Physiol (1985). 2015; 118: 635\u2013645.","DOI":"10.1152\/japplphysiol.00717.2014"},{"key":"i1552-5783-59-8-3739-b27","doi-asserted-by":"crossref","unstructured":"Xiao B, Dubin AE, Bursulaya B, Viswanath V, Jegla TJ, Patapoutian A. Identification of transmembrane domain 5 as a critical molecular determinant of menthol sensitivity in mammalian TRPA1 channels. J Neurosci. 2008; 28: 9640\u20139651.","DOI":"10.1523\/JNEUROSCI.2772-08.2008"},{"key":"i1552-5783-59-8-3739-b28","doi-asserted-by":"crossref","unstructured":"Binshtok AM, Bean BP, Woolf CJ. Inhibition of nociceptors by TRPV1-mediated entry of impermeant sodium channel blockers. Nature. 2007; 449: 607\u2013610.","DOI":"10.1038\/nature06191"},{"key":"i1552-5783-59-8-3739-b29","doi-asserted-by":"crossref","unstructured":"Berge OG. Predictive validity of behavioural animal models for chronic pain. Br J Pharmacol. 2011; 164: 1195\u20131206.","DOI":"10.1111\/j.1476-5381.2011.01300.x"},{"key":"i1552-5783-59-8-3739-b30","doi-asserted-by":"crossref","unstructured":"Kaido M, Kawashima M, Ishida R, Tsubota K. Relationship of corneal pain sensitivity with dry eye symptoms in dry eye with short tear break-up time. Invest Ophthalmol Vis Sci. 2016; 57: 914\u2013919.","DOI":"10.1167\/iovs.15-18447"},{"key":"i1552-5783-59-8-3739-b31","doi-asserted-by":"crossref","unstructured":"Tsubota K, Hata S, Okusawa Y, Egami F, Ohtsuki T, Nakamori K. Quantitative videographic analysis of blinking in normal subjects and patients with dry eye. Arch Ophthalmol. 1996; 114: 715\u2013720.","DOI":"10.1001\/archopht.1996.01100130707012"},{"key":"i1552-5783-59-8-3739-b32","doi-asserted-by":"crossref","unstructured":"Himebaugh NL, Begley CG, Bradley A, Wilkinson JA. Blinking and tear break-up during four visual tasks. Optom Vis Sci. 2009; 86: E106\u2013E114.","DOI":"10.1097\/OPX.0b013e318194e962"},{"key":"i1552-5783-59-8-3739-b33","doi-asserted-by":"crossref","unstructured":"Toshida H, Nguyen DH, Beuerman RW, Murakami A. Evaluation of novel dry eye model: preganglionic parasympathetic denervation in rabbit. Invest Ophthalmol Vis Sci. 2007; 48: 4468\u20134475.","DOI":"10.1167\/iovs.06-1486"},{"key":"i1552-5783-59-8-3739-b34","doi-asserted-by":"crossref","unstructured":"Kaminer J, Powers AS, Horn KG, Hui C, Evinger C. Characterizing the spontaneous blink generator: an animal model. J Neurosci. 2011; 31: 11256\u201311267.","DOI":"10.1523\/JNEUROSCI.6218-10.2011"},{"key":"i1552-5783-59-8-3739-b35","doi-asserted-by":"crossref","unstructured":"Callejo G, Castellanos A, Castany M, et al. Acid-sensing ion channels detect moderate acidifications to induce ocular pain. Pain. 2015; 156: 483\u2013495.","DOI":"10.1097\/01.j.pain.0000460335.49525.17"},{"key":"i1552-5783-59-8-3739-b36","doi-asserted-by":"crossref","unstructured":"Kovacs I, Luna C, Quirce S, et al. Abnormal activity of corneal cold thermoreceptors underlies the unpleasant sensations in dry eye disease. Pain. 2016; 157: 399\u2013417.","DOI":"10.1097\/j.pain.0000000000000455"},{"key":"i1552-5783-59-8-3739-b37","doi-asserted-by":"crossref","unstructured":"Manning KA, Evinger C. Different forms of blinks and their two-stage control. Exp Brain Res. 1986; 64: 579\u2013588.","DOI":"10.1007\/BF00340495"},{"key":"i1552-5783-59-8-3739-b38","doi-asserted-by":"crossref","unstructured":"Stringham JM, Fuld K, Wenzel AJ. Action spectrum for photophobia. J Opt Soc Am A Opt Image Sci Vis. 2003; 20: 1852\u20131858.","DOI":"10.1364\/JOSAA.20.001852"},{"key":"i1552-5783-59-8-3739-b39","doi-asserted-by":"crossref","unstructured":"Yorek MS, Davidson EP, Poolman P, et al. Corneal sensitivity to hyperosmolar eye drops: a novel behavioral assay to assess diabetic peripheral neuropathy. Invest Ophthalmol Vis Sci. 2016; 57: 2412\u20132419.","DOI":"10.1167\/iovs.16-19435"},{"key":"i1552-5783-59-8-3739-b40","doi-asserted-by":"crossref","unstructured":"Tominaga M, Caterina MJ, Malmberg AB, et al. The cloned capsaicin receptor integrates multiple pain-producing stimuli. Neuron. 1998; 21: 531\u2013543.","DOI":"10.1016\/S0896-6273(00)80564-4"},{"key":"i1552-5783-59-8-3739-b41","doi-asserted-by":"crossref","unstructured":"Murata Y, Masuko S. Peripheral and central distribution of TRPV1, substance P and CGRP of rat corneal neurons. Brain Res. 2006; 1085: 87\u201394.","DOI":"10.1016\/j.brainres.2006.02.035"},{"key":"i1552-5783-59-8-3739-b42","doi-asserted-by":"crossref","unstructured":"Alamri A, Bron R, Brock JA, Ivanusic JJ. Transient receptor potential cation channel subfamily V member 1 expressing corneal sensory neurons can be subdivided into at least three subpopulations. Front Neuroanat. 2015; 9: 71.","DOI":"10.3389\/fnana.2015.00071"},{"key":"i1552-5783-59-8-3739-b43","doi-asserted-by":"crossref","unstructured":"Belmonte C, Gallar J, Pozo MA, Rebollo I. Excitation by irritant chemical substances of sensory afferent units in the cat's cornea. J Physiol. 1991; 437: 709\u2013725.","DOI":"10.1113\/jphysiol.1991.sp018621"},{"key":"i1552-5783-59-8-3739-b44","doi-asserted-by":"crossref","unstructured":"Gallar J, Pozo MA, Tuckett RP, Belmonte C. Response of sensory units with unmyelinated fibres to mechanical, thermal and chemical stimulation of the cat's cornea. J Physiol. 1993; 468: 609\u2013622.","DOI":"10.1113\/jphysiol.1993.sp019791"},{"key":"i1552-5783-59-8-3739-b45","doi-asserted-by":"crossref","unstructured":"Gonzalez-Gonzalez O, Bech F, Gallar J, Merayo-Lloves J, Belmonte C. Functional properties of sensory nerve terminals of the mouse cornea. Invest Ophthalmol Vis Sci. 2017; 58: 404\u2013415.","DOI":"10.1167\/iovs.16-20033"},{"key":"i1552-5783-59-8-3739-b46","doi-asserted-by":"crossref","unstructured":"Chen X, Gallar J, Pozo MA, Baeza M, Belmonte C. CO2 stimulation of the cornea: a comparison between human sensation and nerve activity in polymodal nociceptive afferents of the cat. Eur J Neurosci. 1995; 7: 1154\u20131163.","DOI":"10.1111\/j.1460-9568.1995.tb01105.x"},{"key":"i1552-5783-59-8-3739-b47","doi-asserted-by":"crossref","unstructured":"Acosta MC, Belmonte C, Gallar J. Sensory experiences in humans and single-unit activity in cats evoked by polymodal stimulation of the cornea. J Physiol. 2001; 534: 511\u2013525.","DOI":"10.1111\/j.1469-7793.2001.t01-1-00511.x"},{"key":"i1552-5783-59-8-3739-b48","doi-asserted-by":"crossref","unstructured":"Parra A, Gonzalez-Gonzalez O, Gallar J, Belmonte C. Tear fluid hyperosmolality increases nerve impulse activity of cold thermoreceptor endings of the cornea. Pain. 2014; 155: 1481\u20131491.","DOI":"10.1016\/j.pain.2014.04.025"},{"key":"i1552-5783-59-8-3739-b49","doi-asserted-by":"crossref","unstructured":"Parra A, Madrid R, Echevarria D, et al. Ocular surface wetness is regulated by TRPM8-dependent cold thermoreceptors of the cornea. Nat Med. 2010; 16: 1396\u20131399.","DOI":"10.1038\/nm.2264"},{"key":"i1552-5783-59-8-3739-b50","doi-asserted-by":"crossref","unstructured":"Hirata H, Meng ID. Cold-sensitive corneal afferents respond to a variety of ocular stimuli central to tear production: implications for dry eye disease. Invest Ophthalmol Vis Sci. 2010; 51: 3969\u20133976.","DOI":"10.1167\/iovs.09-4744"},{"key":"i1552-5783-59-8-3739-b51","doi-asserted-by":"crossref","unstructured":"Hirata H, Oshinsky ML. Ocular dryness excites two classes of corneal afferent neurons implicated in basal tearing in rats: involvement of transient receptor potential channels. J Neurophysiol. 2012; 107: 1199\u20131209.","DOI":"10.1152\/jn.00657.2011"},{"key":"i1552-5783-59-8-3739-b52","doi-asserted-by":"crossref","unstructured":"Quallo T, Vastani N, Horridge E, et al. TRPM8 is a neuronal osmosensor that regulates eye blinking in mice. Nat Commun. 2015; 6: 7150.","DOI":"10.1038\/ncomms8150"},{"key":"i1552-5783-59-8-3739-b53","doi-asserted-by":"crossref","unstructured":"Zhang X, Mak S, Li L, et al. Direct inhibition of the cold-activated TRPM8 ion channel by Galphaq. Nat Cell Biol. 2012; 14: 851\u2013858.","DOI":"10.1038\/ncb2529"}],"container-title":["Investigative Opthalmology & Visual Science"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/iovs.arvojournals.org\/article.aspx?articleid=2695021","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T21:30:55Z","timestamp":1791927055000},"score":1,"resource":{"primary":{"URL":"http:\/\/iovs.arvojournals.org\/article.aspx?doi=10.1167\/iovs.18-24304"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,7,25]]},"references-count":53,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2018,7,2]]}},"URL":"https:\/\/doi.org\/10.1167\/iovs.18-24304","relation":{},"ISSN":["1552-5783"],"issn-type":[{"value":"1552-5783","type":"print"}],"subject":[],"published":{"date-parts":[[2018,7,25]]}}}