{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T12:40:20Z","timestamp":1791463220346,"version":"4.3.4"},"reference-count":72,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2020,11,19]],"date-time":"2020-11-19T00:00:00Z","timestamp":1605744000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Dry eye disease (DED) is commonly associated with ocular surface inflammation and pain. In this study, we evaluated the effectiveness of repeated instillations of transient receptor potential melastatin 8 (TRPM8) ion channel antagonist M8-B on a mouse model of severe DED induced by the excision of extra-orbital lacrimal and Harderian glands. M8-B was topically administered twice a day from day 7 until day 21 after surgery. Cold and mechanical corneal sensitivities and spontaneous ocular pain were monitored at day 21. Ongoing and cold-evoked ciliary nerve activities were next evaluated by electrophysiological multi-unit extracellular recording. Corneal inflammation and expression of genes related to neuropathic pain and inflammation were assessed in the trigeminal ganglion. We found that DED mice developed a cold allodynia consistent with higher TRPM8 mRNA expression in the trigeminal ganglion (TG). Chronic M8-B instillations markedly reversed both the corneal mechanical allodynia and spontaneous ocular pain commonly associated with persistent DED. M8-B instillations also diminished the sustained spontaneous and cold-evoked ciliary nerve activities observed in DED mice as well as inflammation in the cornea and TG. Overall, our study provides new insight into the effectiveness of TRPM8 blockade for alleviating corneal pain syndrome associated with severe DED, opening a new avenue for ocular pain management.<\/jats:p>","DOI":"10.3390\/ijms21228756","type":"journal-article","created":{"date-parts":[[2020,11,19]],"date-time":"2020-11-19T10:46:26Z","timestamp":1605782786000},"page":"8756","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":44,"title":["TRPM8: A Therapeutic Target for Neuroinflammatory Symptoms Induced by Severe Dry Eye Disease"],"prefix":"10.3390","volume":"21","author":[{"given":"Darine","family":"Fakih","sequence":"first","affiliation":[{"name":"Sorbonne Universit\u00e9, INSERM, CNRS, Institut de la Vision, 17 rue Moreau, F-75012 Paris, France"},{"name":"R&amp;D Department, Laboratoires Th\u00e9a, 12 rue Louis Bi\u00e9rot, F-63000 Clermont-Ferrand, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1743-6698","authenticated-orcid":false,"given":"Christophe","family":"Baudouin","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9, INSERM, CNRS, Institut de la Vision, 17 rue Moreau, F-75012 Paris, France"},{"name":"CHNO des Quinze-Vingts, INSERM-DGOS CIC 1423, 17 rue Moreau, F-75012 Paris, France"},{"name":"Department of Ophthalmology, Ambroise Par\u00e9 Hospital, AP-HP, University of Versailles Saint-Quentin-en-Yvelines, 9 avenue Charles de Gaulle, F-92100 Boulogne-Billancourt, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3855-9523","authenticated-orcid":false,"given":"Annabelle","family":"R\u00e9aux-Le Goazigo","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9, INSERM, CNRS, Institut de la Vision, 17 rue Moreau, F-75012 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2029-9591","authenticated-orcid":false,"given":"St\u00e9phane","family":"M\u00e9lik Parsadaniantz","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9, INSERM, CNRS, Institut de la Vision, 17 rue Moreau, F-75012 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,11,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1016\/j.jtos.2017.05.008","article-title":"TFOS DEWS II Definition and Classification Report","volume":"15","author":"Craig","year":"2017","journal-title":"Ocul. Surf."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1016\/j.jtos.2017.05.003","article-title":"TFOS DEWS II Epidemiology Report","volume":"15","author":"Stapleton","year":"2017","journal-title":"Ocul. Surf."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1016\/j.jtos.2017.05.002","article-title":"TFOS DEWS II pain and sensation report","volume":"15","author":"Belmonte","year":"2017","journal-title":"Ocul. Surf."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"59","DOI":"10.3109\/08820538.2015.1114853","article-title":"Understanding Neuropathic Corneal Pain-Gaps and Current Therapeutic Approaches","volume":"31","author":"Goyal","year":"2016","journal-title":"Semin. Ophthalmol."},{"key":"ref_5","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_6","first-page":"461","article-title":"Sensory and sympathetic innervation of the mammalian cornea. A retrograde tracing study","volume":"30","author":"Marfurt","year":"1989","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1002\/cne.902610309","article-title":"Corneal sensory pathway in the rat: A horseradish peroxidase tracing study","volume":"261","author":"Marfurt","year":"1987","journal-title":"J. Comp. Neurol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1007\/s40135-015-0073-9","article-title":"What Causes Eye Pain?","volume":"3","author":"Belmonte","year":"2015","journal-title":"Curr. Ophthalmol. Rep."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3969","DOI":"10.1167\/iovs.09-4744","article-title":"Cold-sensitive corneal afferents respond to a variety of ocular stimuli central to tear production: Implications for dry eye disease","volume":"51","author":"Hirata","year":"2010","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1396","DOI":"10.1038\/nm.2264","article-title":"Ocular surface wetness is regulated by TRPM8-dependent cold thermoreceptors of the cornea","volume":"16","author":"Parra","year":"2010","journal-title":"Nat. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"7150","DOI":"10.1038\/ncomms8150","article-title":"TRPM8 is a neuronal osmosensor that regulates eye blinking in mice","volume":"6","author":"Quallo","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3888","DOI":"10.1167\/iovs.09-5119","article-title":"Cold thermoreceptors, unexpected players in tear production and ocular dryness sensations","volume":"52","author":"Belmonte","year":"2011","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Gonz\u00e1lez-Mu\u00f1iz, R., Bonache, M.A., Mart\u00edn-Escura, C., and G\u00f3mez-Monterrey, I. (2019). Recent Progress in TRPM8 Modulation: An Update. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20112618"},{"key":"ref_14","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_15","doi-asserted-by":"crossref","first-page":"8177","DOI":"10.1523\/JNEUROSCI.0654-19.2019","article-title":"Role of TRPM8 Channels in Altered Cold Sensitivity of Corneal Primary Sensory Neurons Induced by Axonal Damage","volume":"39","author":"Ugarte","year":"2019","journal-title":"J. Neurosci. Off. J. Soc. Neurosci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1186\/1744-8069-8-66","article-title":"Expression of the transient receptor potential channels TRPV1, TRPA1 and TRPM8 in mouse trigeminal primary afferent neurons innervating the dura","volume":"8","author":"Huang","year":"2012","journal-title":"Mol. Pain"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1016\/j.neuron.2007.04.017","article-title":"Attenuated cold sensitivity in TRPM8 null mice","volume":"54","author":"Colburn","year":"2007","journal-title":"Neuron"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1016\/j.neuron.2007.02.024","article-title":"TRPM8 is required for cold sensation in mice","volume":"54","author":"Dhaka","year":"2007","journal-title":"Neuron"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1038\/nature05910","article-title":"The menthol receptor TRPM8 is the principal detector of environmental cold","volume":"448","author":"Bautista","year":"2007","journal-title":"Nature"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/S0014-2999(01)01303-6","article-title":"Pathobiology of neuropathic pain","volume":"429","author":"Zimmermann","year":"2001","journal-title":"Eur. J. Pharmacol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0014-2999(01)01302-4","article-title":"The clinical picture of neuropathic pain","volume":"429","author":"Jensen","year":"2001","journal-title":"Eur. J. Pharmacol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1007\/s10787-016-0288-x","article-title":"TRP channels: Potential drug target for neuropathic pain","volume":"24","author":"Marwaha","year":"2016","journal-title":"Inflammopharmacology"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Caspani, O., Zurborg, S., Labuz, D., and Heppenstall, P.A. (2009). The Contribution of TRPM8 and TRPA1 Channels to Cold Allodynia and Neuropathic Pain. PLOS ONE, 4.","DOI":"10.1371\/journal.pone.0007383"},{"key":"ref_24","unstructured":"Frederick, J., Buck, M.E., Matson, D.J., and Cortright, D.N. (2020, August 31). Increased TRPA1, TRPM8, and TRPV2 Expression in Dorsal Root Ganglia by Nerve Injury, Available online: http:\/\/pubmed.ncbi.nlm.nih.gov\/17517374\/."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"13680","DOI":"10.1523\/JNEUROSCI.2203-07.2007","article-title":"TRPM8 mechanism of cold allodynia after chronic nerve injury","volume":"27","author":"Xing","year":"2007","journal-title":"J. Neurosci. Off. J. Soc. Neurosci."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Koh, W.U., Choi, S.-S., Kim, J.H., Yoon, H.J., Ahn, H.-S., Lee, S.K., Leem, J.G., Song, J.G., and Shin, J.W. (2016). The preventive effect of resiniferatoxin on the development of cold hypersensitivity induced by spinal nerve ligation: Involvement of TRPM8. BMC Neurosci., 17.","DOI":"10.1186\/s12868-016-0273-8"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Knowlton, W.M., Daniels, R.L., Palkar, R., McCoy, D.D., and McKemy, D.D. (2011). Pharmacological Blockade of TRPM8 Ion Channels Alters Cold and Cold Pain Responses in Mice. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0025894"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1021\/jm101075v","article-title":"Design and optimization of benzimidazole-containing transient receptor potential melastatin 8 (TRPM8) antagonists","volume":"54","author":"Parks","year":"2011","journal-title":"J. Med. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1631\/jzus.B1400189","article-title":"Antinociceptive activity of transient receptor potential channel TRPV1, TRPA1, and TRPM8 antagonists in neurogenic and neuropathic pain models in mice","volume":"16","author":"Filipek","year":"2015","journal-title":"J. Zhejiang Univ. Sci. B"},{"key":"ref_30","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_31","doi-asserted-by":"crossref","unstructured":"De Caro, C., Cristiano, C., Avagliano, C., Bertamino, A., Ostacolo, C., Campiglia, P., Gomez-Monterrey, I., La Rana, G., Gualillo, O., and Calignano, A. (2019). Characterization of New TRPM8 Modulators in Pain Perception. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20225544"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1097\/j.pain.0000000000000455","article-title":"Abnormal activity of corneal cold thermoreceptors underlies the unpleasant sensations in dry eye disease","volume":"157","author":"Luna","year":"2016","journal-title":"Pain"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1152\/jn.00222.2013","article-title":"Dry eye modifies the thermal and menthol responses in rat corneal primary afferent cool cells","volume":"110","author":"Kurose","year":"2013","journal-title":"J. Neurophysiol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1199","DOI":"10.1152\/jn.00657.2011","article-title":"Ocular dryness excites two classes of corneal afferent neurons implicated in basal tearing in rats: Involvement of transient receptor potential channels","volume":"107","author":"Hirata","year":"2012","journal-title":"J. Neurophysiol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"7034","DOI":"10.1167\/iovs.12-10025","article-title":"Menthol activation of corneal cool cells induces TRPM8-mediated lacrimation but not nociceptive responses in rodents","volume":"53","author":"Robbins","year":"2012","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Weyer, A.D., and Lehto, S.G. (2017). Development of TRPM8 Antagonists to Treat Chronic Pain and Migraine. Pharmaceuticals, 10.","DOI":"10.3390\/ph10020037"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Yang, J.M., Li, F., Liu, Q., R\u00fcedi, M., Wei, E.T., Lentsman, M., Lee, H.S., Choi, W., Kim, S.J., and Yoon, K.C. (2017). A novel TRPM8 agonist relieves dry eye discomfort. BMC Ophthalmol., 17.","DOI":"10.1186\/s12886-017-0495-2"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1159","DOI":"10.1093\/brain\/awh134","article-title":"Topical menthol\u2014A human model for cold pain by activation and sensitization of C nociceptors","volume":"127","author":"Wasner","year":"2004","journal-title":"Brain"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1016\/j.pain.2006.01.026","article-title":"Psychophysical study of the effects of topical application of menthol in healthy volunteers","volume":"122","author":"Hatem","year":"2006","journal-title":"Pain"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1111\/j.1469-7793.2001.t01-1-00511.x","article-title":"Sensory experiences in humans and single-unit activity in cats evoked by polymodal stimulation of the cornea","volume":"534","author":"Acosta","year":"2001","journal-title":"J. Physiol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1186\/s12974-019-1656-4","article-title":"Chronic dry eye induced corneal hypersensitivity, neuroinflammatory responses, and synaptic plasticity in the mouse trigeminal brainstem","volume":"16","author":"Fakih","year":"2019","journal-title":"J. Neuroinflamm."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2971","DOI":"10.1167\/iovs.08-1734","article-title":"Conjunctival and corneal pneumatic sensitivity is associated with signs and symptoms of ocular dryness","volume":"49","author":"Situ","year":"2008","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2837","DOI":"10.1523\/JNEUROSCI.1943-12.2013","article-title":"A sensory-labeled line for cold: TRPM8-expressing sensory neurons define the cellular basis for cold, cold pain, and cooling-mediated analgesia","volume":"33","author":"Knowlton","year":"2013","journal-title":"J. Neurosci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"955","DOI":"10.1097\/00001756-200506210-00015","article-title":"TRPA1 and TRPM8 activation in humans: Effects of cinnamaldehyde and menthol","volume":"16","author":"Namer","year":"2005","journal-title":"Neuroreport"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1591","DOI":"10.1016\/j.cub.2006.07.061","article-title":"Analgesia mediated by the TRPM8 cold receptor in chronic neuropathic pain","volume":"16","author":"Proudfoot","year":"2006","journal-title":"Curr. Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"946","DOI":"10.1016\/j.jid.2017.11.004","article-title":"Merkel Cells Sense Cooling with TRPM8 Channels","volume":"138","author":"Bouvier","year":"2018","journal-title":"J. Investig. Dermatol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.neulet.2017.04.018","article-title":"Vagus nerve is involved in the changes in body temperature induced by intragastric administration of 1,8-cineole via TRPM8 in mice","volume":"650","author":"Urata","year":"2017","journal-title":"Neurosci. Lett."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2086","DOI":"10.1523\/JNEUROSCI.5606-11.2012","article-title":"Pharmacological Blockade of the Cold Receptor TRPM8 Attenuates Autonomic and Behavioral Cold Defenses and Decreases Deep Body Temperature","volume":"32","author":"Almeida","year":"2012","journal-title":"J. Neurosci."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2191","DOI":"10.1152\/jn.00126.2018","article-title":"Dry eye sensitizes cool cells to capsaicin-induced changes in activity via TRPV1","volume":"121","author":"Hatta","year":"2019","journal-title":"J. Neurophysiol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"3739","DOI":"10.1167\/iovs.18-24304","article-title":"TRPV1 and TRPM8 Channels and Nocifensive Behavior in a Rat Model for Dry Eye","volume":"59","author":"Bereiter","year":"2018","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"942","DOI":"10.1097\/j.pain.0000000000000135","article-title":"Sensitization of trigeminal brainstem pathways in a model for tear deficient dry eye","volume":"156","author":"Rahman","year":"2015","journal-title":"Pain"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1016\/S1542-0124(12)70112-X","article-title":"Nerves and sensations from the eye surface","volume":"2","author":"Belmonte","year":"2004","journal-title":"Ocul Surf."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1167\/iovs.16-20033","article-title":"Functional Properties of Sensory Nerve Terminals of the Mouse Cornea","volume":"58","author":"Bech","year":"2017","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1111\/j.1469-7793.2001.0493a.x","article-title":"Differences between nerve terminal impulses of polymodal nociceptors and cold sensory receptors of the guinea-pig cornea","volume":"533","author":"Brock","year":"2001","journal-title":"J. Physiol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"2281","DOI":"10.1167\/iovs.18-24007","article-title":"Functional and Morphologic Alterations in Mechanical, Polymodal, and Cold Sensory Nerve Fibers of the Cornea Following Photorefractive Keratectomy","volume":"59","author":"Bech","year":"2018","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1136\/bjophthalmol-2015-307415","article-title":"Revisiting the vicious circle of dry eye disease: A focus on the pathophysiology of meibomian gland dysfunction","volume":"100","author":"Baudouin","year":"2016","journal-title":"Br. J. Ophthalmol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1266","DOI":"10.1007\/s10753-018-0774-y","article-title":"Cold Stimuli Facilitate Inflammatory Responses Through Transient Receptor Potential Melastatin 8 (TRPM8) in Primary Airway Epithelial Cells of Asthmatic Mice","volume":"41","author":"Liu","year":"2018","journal-title":"Inflammation"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1093\/abbs\/gmy033","article-title":"Inhibition of transient receptor potential melastatin 8 alleviates airway inflammation and remodeling in a murine model of asthma with cold air stimulus","volume":"50","author":"Liu","year":"2018","journal-title":"Acta Biochim. Biophys. Sin."},{"key":"ref_59","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_60","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1016\/j.jtos.2017.03.006","article-title":"TFOS DEWS II Tear Film Report","volume":"15","author":"Willcox","year":"2017","journal-title":"Ocul. Surf."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Nicolle, P., Liang, H., Reboussin, E., Rabut, G., Warcoin, E., Brignole-Baudouin, F., Melik-Parsadaniantz, S., Baudouin, C., Labbe, A., and Reaux-Le Goazigo, A. (2018). Proinflammatory Markers, Chemokines, and Enkephalin in Patients Suffering from Dry Eye Disease. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19041221"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1308","DOI":"10.1038\/emboj.2009.57","article-title":"The mechano-activated K+ channels TRAAK and TREK-1 control both warm and cold perception","volume":"28","author":"Zimmermann","year":"2009","journal-title":"EMBO J."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"3120","DOI":"10.1523\/JNEUROSCI.4778-08.2009","article-title":"Variable threshold of trigeminal cold-thermosensitive neurons is determined by a balance between TRPM8 and Kv1 potassium channels","volume":"29","author":"Madrid","year":"2009","journal-title":"J. Neurosci. Off. J. Soc. Neurosci."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1126\/science.1156916","article-title":"The cell and molecular basis of mechanical, cold, and inflammatory pain","volume":"321","author":"Abrahamsen","year":"2008","journal-title":"Science"},{"key":"ref_65","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_66","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1038\/32897","article-title":"Primary afferent tachykinins are required to experience moderate to intense pain","volume":"392","author":"Cao","year":"1998","journal-title":"Nature"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1007\/BF00176775","article-title":"The non-peptide NK1 receptor antagonist SR140333 produces long-lasting inhibition of neurogenic inflammation, but does not influence acute chemo- or thermonociception in rats","volume":"352","author":"Amann","year":"1995","journal-title":"Naunyn Schmiedebergs Arch. Pharmacol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.bbr.2010.04.015","article-title":"Topical application of L-menthol induces heat analgesia, mechanical allodynia, and a biphasic effect on cold sensitivity in rats","volume":"212","author":"Klein","year":"2010","journal-title":"Behav. Brain Res."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1038\/nmeth.1455","article-title":"Coding of facial expressions of pain in the laboratory mouse","volume":"7","author":"Langford","year":"2010","journal-title":"Nat. Methods"},{"key":"ref_70","first-page":"42","article-title":"Using the Mouse Grimace Scale to reevaluate the efficacy of postoperative analgesics in laboratory mice","volume":"51","author":"Matsumiya","year":"2012","journal-title":"J. Am. Assoc. Lab. Anim. Sci."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"5473","DOI":"10.1167\/iovs.06-0728","article-title":"New Tools for the Evaluation of Toxic Ocular Surface Changes in the Rat","volume":"48","author":"Pauly","year":"2007","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1002\/ejp.1332","article-title":"Effects of corneal injury on ciliary nerve fibre activity and corneal nociception in mice: A behavioural and electrophysiological study","volume":"23","author":"Joubert","year":"2019","journal-title":"Eur. J. Pain"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/22\/8756\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:34:33Z","timestamp":1760178873000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/22\/8756"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,11,19]]},"references-count":72,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2020,11]]}},"alternative-id":["ijms21228756"],"URL":"https:\/\/doi.org\/10.3390\/ijms21228756","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,11,19]]}}}