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However, the effectiveness of TRPM8 modulators for pain relief is still a matter of discussion, since structurally diverse modulators lead to different results, depending on the animal pain model. In this work, we described the antinociceptive activity of a \u03b2\u2013lactam derivative, RGM8-51, showing good TRPM8 antagonist activity, and selectivity against related thermoTRP channels and other pain-mediating receptors. In primary cultures of rat dorsal root ganglion (DRG) neurons, RGM8-51 potently reduced menthol-evoked neuronal firing without affecting the major ion conductances responsible for action potential generation. This compound has in vivo antinociceptive activity in response to cold, in a mouse model of oxaliplatin-induced peripheral neuropathy. In addition, it reduces cold, mechanical and heat hypersensitivity in a rat model of neuropathic pain arising after chronic constriction of the sciatic nerve. Furthermore, RGM8-51 exhibits mechanical hypersensitivity-relieving activity, in a mouse model of NTG-induced hyperesthesia. Taken together, these preclinical results substantiate that this TRPM8 antagonist is a promising pharmacological tool to study TRPM8-related diseases.<\/jats:p>","DOI":"10.3390\/ijms23052692","type":"journal-article","created":{"date-parts":[[2022,2,28]],"date-time":"2022-02-28T20:11:14Z","timestamp":1646079074000},"page":"2692","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["\u03b2\u2013Lactam TRPM8 Antagonist RGM8-51 Displays Antinociceptive Activity in Different Animal Models"],"prefix":"10.3390","volume":"23","author":[{"given":"Cristina","family":"Mart\u00edn-Escura","sequence":"first","affiliation":[{"name":"Instituto de Qu\u00edmica M\u00e9dica (IQM-CSIC), 28006 Madrid, Spain"},{"name":"Alodia Farmac\u00e9utica SL, 28108 Alcobendas, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8035-0179","authenticated-orcid":false,"given":"Alicia","family":"Medina-Peris","sequence":"additional","affiliation":[{"name":"IDiBE, Universidad Miguel Hern\u00e1ndez, 03202 Elche, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9204-0215","authenticated-orcid":false,"given":"Luke A.","family":"Spear","sequence":"additional","affiliation":[{"name":"Instituto de Qu\u00edmica M\u00e9dica (IQM-CSIC), 28006 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9872-6050","authenticated-orcid":false,"given":"Roberto","family":"de la Torre Mart\u00ednez","sequence":"additional","affiliation":[{"name":"IDiBE, Universidad Miguel Hern\u00e1ndez, 03202 Elche, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0595-073X","authenticated-orcid":false,"given":"Luis A.","family":"Olivos-Or\u00e9","sequence":"additional","affiliation":[{"name":"Departamento de Farmacolog\u00eda y Toxicolog\u00eda, Facultad de Veterinaria, Universidad Complutense de Madrid, 28040 Madrid, Spain"},{"name":"Instituto Universitario de Investigaci\u00f3n en Neuroqu\u00edmica, Universidad Complutense de Madrid, 28040 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mar\u00eda Victoria","family":"Barahona","sequence":"additional","affiliation":[{"name":"Departamento de Farmacolog\u00eda y Toxicolog\u00eda, Facultad de Veterinaria, Universidad Complutense de Madrid, 28040 Madrid, Spain"},{"name":"Instituto Universitario de Investigaci\u00f3n en Neuroqu\u00edmica, Universidad Complutense de Madrid, 28040 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6906-8108","authenticated-orcid":false,"given":"Sara","family":"Gonz\u00e1lez-Rodr\u00edguez","sequence":"additional","affiliation":[{"name":"IDiBE, Universidad Miguel Hern\u00e1ndez, 03202 Elche, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5412-8611","authenticated-orcid":false,"given":"Gregorio","family":"Fern\u00e1ndez-Ballester","sequence":"additional","affiliation":[{"name":"IDiBE, Universidad Miguel Hern\u00e1ndez, 03202 Elche, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2741-1427","authenticated-orcid":false,"given":"Asia","family":"Fern\u00e1ndez-Carvajal","sequence":"additional","affiliation":[{"name":"IDiBE, Universidad Miguel Hern\u00e1ndez, 03202 Elche, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9720-9190","authenticated-orcid":false,"given":"Antonio R.","family":"Artalejo","sequence":"additional","affiliation":[{"name":"Departamento de Farmacolog\u00eda y Toxicolog\u00eda, Facultad de Veterinaria, Universidad Complutense de Madrid, 28040 Madrid, Spain"},{"name":"Instituto Universitario de Investigaci\u00f3n en Neuroqu\u00edmica, Universidad Complutense de Madrid, 28040 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2973-6607","authenticated-orcid":false,"given":"Antonio","family":"Ferrer-Montiel","sequence":"additional","affiliation":[{"name":"IDiBE, Universidad Miguel Hern\u00e1ndez, 03202 Elche, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8833-4328","authenticated-orcid":false,"given":"Rosario","family":"Gonz\u00e1lez-Mu\u00f1iz","sequence":"additional","affiliation":[{"name":"Instituto de Qu\u00edmica M\u00e9dica (IQM-CSIC), 28006 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,2,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Liu, Y., Mikrani, R., He, Y., Faran Ashraf Baig, M.M., Abbas, M., Naveed, M., Tang, M., Zhang, Q., Li, C., and Zhou, X. (2020). TRPM8 channels: A review of distribution and clinical role. Eur. J. Pharmacol., 882.","DOI":"10.1016\/j.ejphar.2020.173312"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"10006","DOI":"10.1021\/acs.jmedchem.6b00305","article-title":"Transient Receptor Potential Melastatin 8 Channel (TRPM8) Modulation: Cool Entryway for Treating Pain and Cancer","volume":"59","year":"2016","journal-title":"J. Med. Chem."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Gonzalez-Mu\u00f1iz, R., Bonache, M.A., Martin-Escura, C., and Gomez-Monterrey, I. (2019). Recent Progress in TRPM8 Modulation: An Update. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20112618"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"11435","DOI":"10.1523\/JNEUROSCI.2327-16.2016","article-title":"New insight in cold pain: Role of ion channels, modulation, and clinical perspectives","volume":"36","author":"Lolignier","year":"2016","journal-title":"J. Neurosci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/0304-3959(88)90209-6","article-title":"A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man","volume":"33","author":"Bennett","year":"1988","journal-title":"Pain"},{"key":"ref_6","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_7","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.brainresbull.2017.08.002","article-title":"Downregulations of TRPM8 expression and membrane trafficking in dorsal root ganglion mediate the attenuation of cold hyperalgesia in CCI rats induced by GFR\u03b13 knockdown","volume":"135","author":"Su","year":"2017","journal-title":"Brain Res. Bull."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Su, L., Wang, C., Yu, Y.-H., Ren, Y.-Y., Xie, K.-L., and Wang, G.-L. (2011). Role of TRPM8 in dorsal root ganglion in nerve injury-induced chronic pain. BMC Neurosci., 12.","DOI":"10.1186\/1471-2202-12-120"},{"key":"ref_9","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_10","doi-asserted-by":"crossref","first-page":"1287","DOI":"10.2147\/JPR.S197168","article-title":"Intrathecal TRPM8 blocking attenuates cold hyperalgesia via PKC and NF-\u03baB signaling in the dorsal root ganglion of rats with neuropathic pain","volume":"12","author":"Cao","year":"2019","journal-title":"J. Pain Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1007\/s00210-015-1090-9","article-title":"AMG2850, a potent and selective TRPM8 antagonist, is not effective in rat models of inflammatory mechanical hypersensitivity and neuropathic tactile allodynia","volume":"388","author":"Lehto","year":"2015","journal-title":"Naunyn-Schmiedeberg\u2019s Arch. Pharmacol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"9672","DOI":"10.1021\/acs.jmedchem.0c00816","article-title":"Exploration of TRPM8 Binding Sites by \u03b2-Carboline-Based Antagonists and Their In Vitro Characterization and In Vivo Analgesic Activities","volume":"63","author":"Bertamino","year":"2020","journal-title":"J. Med. Chem."},{"key":"ref_13","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_14","doi-asserted-by":"crossref","first-page":"419","DOI":"10.3322\/caac.21204","article-title":"Chemotherapy-Induced Peripheral Neurotoxicity: A Critical Analysis","volume":"63","author":"Park","year":"2013","journal-title":"CA Cancer J. Clin."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2611","DOI":"10.1111\/liv.15002","article-title":"Peripheral neuropathy after viral eradication with direct-acting antivirals in chronic HCV hepatitis: A prospective study","volume":"41","author":"Zanone","year":"2021","journal-title":"Liver Int."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Egan, K.E., Caldwell, G.M., and Eckmann, M.S. (2021). HIV Neuropathy-a Review of Mechanisms, Diagnosis, and Treatment of Pain. Curr. Pain Headache Rep., 25.","DOI":"10.1007\/s11916-021-00971-2"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"127","DOI":"10.2174\/1876386301306010127","article-title":"Transient receptor potential channels in chemotherapy-induced neuropathy","volume":"6","author":"Nassini","year":"2013","journal-title":"Open Pain J."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Rimola, V., Osthues, T., Koenigs, V., Geisslinger, G., and Sisignano, M. (2021). Oxaliplatin causes transient changes in TRPM8 channel activity. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22094962"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1016\/j.pharep.2016.03.001","article-title":"Involvement of c-Myc-mediated transient receptor potential melastatin 8 expression in oxaliplatin-induced cold allodynia in mice","volume":"68","author":"Mizoguchi","year":"2016","journal-title":"Pharmacol. Rep."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"309","DOI":"10.2174\/1567202613666160601144254","article-title":"TRPA1 and TRPM8 Receptors May Promote Local Vasodilation that Aggravates Oxaliplatin-Induced Peripheral Neuropathy Amenable to 17\u03b2-Estradiol Treatment","volume":"13","author":"Pan","year":"2016","journal-title":"Curr. Neurovasc. Res."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Wu, B., Su, X., Zhang, W., Zhang, Y.-H., Feng, X., Ji, Y.-H., and Tan, Z.-Y. (2021). Oxaliplatin depolarizes the IB4- dorsal root ganglion neurons to drive the development of neuropathic pain through TRPM8 in mice. Front. Mol. Neurosci., 14.","DOI":"10.3389\/fnmol.2021.690858"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Kawashiri, T., Egashira, N., Kurobe, K., Tsutsumi, K., Yamashita, Y., Ushio, S., Yano, T., and Oishi, R. (2012). L type Ca2+ channel blockers prevent oxaliplatin-induced cold hyperalgesia and TRPM8 overexpression in rats. Mol. Pain, 8.","DOI":"10.1186\/1744-8069-8-7"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2297","DOI":"10.1016\/j.pain.2013.05.033","article-title":"Systemic morphine treatment induces changes in firing patterns and responses of nociceptive afferent fibers in mouse glabrous skin","volume":"154","author":"Hogan","year":"2013","journal-title":"Pain"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1016\/j.jpain.2016.10.015","article-title":"Sustained Morphine Administration Induces TRPM8-Dependent Cold Hyperalgesia","volume":"18","author":"Gong","year":"2017","journal-title":"J. Pain"},{"key":"ref_25","first-page":"515","article-title":"Role of transient receptor potential melastatin 8 channels in migraine mechanism in rats","volume":"17","author":"Qin","year":"2015","journal-title":"Zhongguo Dangdai Erke Zazhi"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Ling, Y.H., Chen, S.P., Fann, C.S.J., Wang, S.J., and Wang, Y.F. (2019). TRPM8 genetic variant is associated with chronic migraine and allodynia. J. Headache Pain, 20.","DOI":"10.1186\/s10194-019-1064-2"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1247","DOI":"10.1007\/s11033-019-04593-1","article-title":"rs2651899 variant is associated with risk for migraine without aura from North Indian population","volume":"46","author":"Kaur","year":"2019","journal-title":"Mol. Biol. Rep."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1134\/S0362119711020101","article-title":"Single-nucleotide polymorphism rs11562975 of the thermosensitive ion channel TRPM8 gene and human sensitivity to cold and menthol","volume":"37","author":"Kozyreva","year":"2011","journal-title":"Hum. Physiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"8186","DOI":"10.1021\/acs.jmedchem.8b00518","article-title":"Discovery of TRPM8 Antagonist (S)-6-(((3-Fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)carbamoyl)nicotinic Acid (AMG 333), a Clinical Candidate for the Treatment of Migraine","volume":"61","author":"Horne","year":"2018","journal-title":"J. Med. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"De la Torre-Martinez, R., Bonache, M.A., Llabres-Campaner, P.J., Balsera, B., Fernandez-Carvajal, A., Fernandez-Ballester, G., Ferrer-Montiel, A., Perez de Vega, M.J., and Gonzalez-Muniz, R. (2017). Synthesis, high-throughput screening and pharmacological characterization of \u03b2\u2013lactam derivatives as TRPM8 antagonists. Sci. Rep., 7.","DOI":"10.1038\/s41598-017-10913-x"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Bonache, M.A., Martin-Escura, C., de la Torre Martinez, R., Medina, A., Gonzalez-Rodriguez, S., Francesch, A., Cuevas, C., Roa, A.M., Fernandez-Ballester, G., and Ferrer-Montiel, A. (2020). Highly functionalized \u03b2\u2013lactams and 2-ketopiperazines as TRPM8 antagonists with antiallodynic activity. Sci. Rep., 10.","DOI":"10.1038\/s41598-020-70691-x"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1593","DOI":"10.1021\/ol070533d","article-title":"Exceptional Stereoselectivity in the Synthesis of 1,3,4-Trisubstituted 4-Carboxy \u03b2\u2013Lactam Derivatives from Amino Acids","volume":"9","year":"2007","journal-title":"Org. Lett."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"F803","DOI":"10.1152\/ajprenal.90269.2008","article-title":"AMTB, a TRPM8 channel blocker: Evidence in rats for activity in overactive bladder and painful bladder syndrome","volume":"295","author":"Lashinger","year":"2008","journal-title":"Am. J. Physiol. Ren. Physiol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1007\/978-981-13-1756-9_2","article-title":"TRP Channels in Nociception and Pathological Pain","volume":"1099","author":"Hung","year":"2018","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"999","DOI":"10.1517\/13543776.2012.711320","article-title":"Advances in modulating thermosensory TRP channels","volume":"22","author":"Messeguer","year":"2012","journal-title":"Expert Opin. Ther. Pat."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1021\/cn100094b","article-title":"ASIC3 Channels in Multimodal Sensory Perception","volume":"2","author":"Li","year":"2011","journal-title":"ACS Chem. Neurosci."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Schou, W.S., Ashina, S., Amin, F.M., Goadsby, P.J., and Ashina, M. (2017). Calcitonin gene-related peptide and pain: A systematic review. J. Headache Pain, 18.","DOI":"10.1186\/s10194-017-0741-2"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.coph.2008.12.007","article-title":"CGRP receptors in the control of pain and inflammation","volume":"9","author":"Benemei","year":"2009","journal-title":"Curr. Opin. Pharmacol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/j.neuroscience.2013.12.028","article-title":"Spinal gene expression profiling and pathways analysis of a CB2 agonist (MDA7)-targeted prevention of paclitaxel-induced neuropathy","volume":"260","author":"Xu","year":"2014","journal-title":"Neuroscience"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1265","DOI":"10.1038\/nn.2632","article-title":"Anandamide suppresses pain initiation through a peripheral endocannabinoid mechanism","volume":"13","author":"Clapper","year":"2010","journal-title":"Nat. Neurosci."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1016\/j.pain.2008.06.007","article-title":"Cannabinoid receptor CB2 localisation and agonist-mediated inhibition of capsaicin responses in human sensory neurons","volume":"138","author":"Anand","year":"2008","journal-title":"Pain"},{"key":"ref_42","first-page":"222","article-title":"Rat dorsal root ganglia express m1-m4 muscarinic receptor proteins","volume":"4","author":"Bernardini","year":"1999","journal-title":"J. Peripher. Nerv. Syst."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1023\/A:1013368509855","article-title":"Identification and characterization of muscarinic acetylcholine receptor subtypes expressed in human skin melanocytes","volume":"228","author":"Buchli","year":"2001","journal-title":"Mol. Cell. Biochem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1159\/000086750","article-title":"Identification and Functional Characterization of the Muscarinic Receptor M3 in the Human Keratinocyte Cell Line HaCaT","volume":"180","author":"Metzger","year":"2005","journal-title":"Cells Tissues Organs"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1002\/prot.20251","article-title":"Making optimal use of empirical energy functions: Force-field parameterization in crystal space","volume":"57","author":"Krieger","year":"2004","journal-title":"Proteins Struct. Funct. Bioinform."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1002\/prot.10104","article-title":"Increasing the precision of comparative models with yasara NOVA-a self-parameterizing force field","volume":"47","author":"Krieger","year":"2002","journal-title":"Proteins Struct. Funct. Genet."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1126\/science.aan4325","article-title":"Structure of the cold- and menthol-sensing ion channel TRPM8","volume":"359","author":"Yin","year":"2018","journal-title":"Science"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1434","DOI":"10.1126\/science.aax6672","article-title":"Structural insights into TRPM8 inhibition and desensitization","volume":"365","author":"Diver","year":"2019","journal-title":"Science"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"587","DOI":"10.3109\/0284186X.2014.995775","article-title":"Chemotherapy-induced peripheral neuropathy in patients treated with taxanes and platinum derivatives","volume":"54","author":"Ewertz","year":"2015","journal-title":"Acta Oncol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1021\/acschemneuro.9b00404","article-title":"Structure-Based Design of Novel Biphenyl Amide Antagonists of Human Transient Receptor Potential Cation Channel Subfamily M Member 8 Channels with Potential Implications in the Treatment of Sensory Neuropathies","volume":"11","author":"Journigan","year":"2020","journal-title":"ACS Chem. Neurosci."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Gavva, N.R., Sandrock, R., Arnold, G.E., Davis, M., Lamas, E., Lindvay, C., Li, C.-M., Smith, B., Gabriel, K., and Vargas, G. (2019). Reduced TRPM8 expression underpins reduced migraine risk and attenuated cold pain sensation in humans. Sci. Rep., 9.","DOI":"10.1038\/s41598-019-56295-0"},{"key":"ref_52","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_53","doi-asserted-by":"crossref","unstructured":"Benemei, S., and Dussor, G. (2019). TRP Channels and Migraine: Recent Developments and New Therapeutic Opportunities. Pharmaceuticals, 12.","DOI":"10.3390\/ph12020054"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1111\/j.1742-1241.2009.02215.x","article-title":"Cutaneous application of menthol 10% solution as an abortive treatment of migraine without aura: A randomised, double-blind, placebo-controlled, crossed-over study","volume":"64","author":"Haghighi","year":"2010","journal-title":"Int. J. Clin. Pract."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"9.60.1","DOI":"10.1002\/cpns.33","article-title":"Animal Model of Chronic Migraine-Associated Pain","volume":"80","author":"Moye","year":"2017","journal-title":"Curr. Protoc. Neurosci."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1048","DOI":"10.1177\/0333102415623070","article-title":"The effects of acute and preventive migraine therapies in a mouse model of chronic migraine","volume":"36","author":"Tipton","year":"2016","journal-title":"Cephalalgia"},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Wen, Q., Zhang, D., Qin, G., Chen, L., Wang, Y., Pan, Q., Tian, R., Zhou, J., and Wang, Y. (2021). MicroRNA-155-5p promotes neuroinflammation and central sensitization via inhibiting SIRT1 in a nitroglycerin-induced chronic migraine mouse model. J. Neuroinflamm., 18.","DOI":"10.1186\/s12974-021-02342-5"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"2659","DOI":"10.1074\/jbc.M114.610824","article-title":"The TRPM8 protein is a testosterone receptor: I. Biochemical evidence for direct TRPM8-testosterone interactions","volume":"290","author":"Asuthkar","year":"2015","journal-title":"J. Biol. Chem."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"2670","DOI":"10.1074\/jbc.M114.610873","article-title":"The TRPM8 Protein Is a Testosterone Receptor. II. Functional Evidence for an Ionotropic Effect of Testosterone on TRPM8","volume":"290","author":"Asuthkar","year":"2015","journal-title":"J. Biol. Chem."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"10887","DOI":"10.1096\/fj.202000794R","article-title":"TRPM8 as the rapid testosterone signaling receptor: Implications in the regulation of dimorphic sexual and social behaviors","volume":"34","author":"Mohandass","year":"2020","journal-title":"FASEB J."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1112","DOI":"10.1021\/tx034223p","article-title":"Stereoselective synthesis of natural N-(1-deoxy-D-\u03b2-fructos-1-yl)-L- amino acids and their effect on lead decorporation","volume":"17","author":"Huo","year":"2004","journal-title":"Chem. Res. Toxicol."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Arribas-Blazquez, M., Olivos-Ore, L.A., Barahona, M.V., Sanchez de la Muela, M., Solar, V., Jimenez, E., Gualix, J., McIntosh, J.M., Ferrer-Montiel, A., and Miras-Portugal, M.T. (2019). Overexpression of P2X3 and P2X7 receptors and TRPV1 channels in adrenomedullary chromaffin cells in a rat model of neuropathic pain. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20010155"},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Nikolaeva-Koleva, M., Butron, L., Gonzalez-Rodriguez, S., Devesa, I., Valente, P., Serafini, M., Genazzani, A.A., Pirali, T., Ballester, G.F., and Fernandez-Carvajal, A. (2021). A capsaicinoid-based soft drug, AG1529, for attenuating TRPV1-mediated histaminergic and inflammatory sensory neuron excitability. Sci. Rep., 11.","DOI":"10.1038\/s41598-020-80725-z"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/5\/2692\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:29:43Z","timestamp":1760135383000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/5\/2692"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,2,28]]},"references-count":63,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2022,3]]}},"alternative-id":["ijms23052692"],"URL":"https:\/\/doi.org\/10.3390\/ijms23052692","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,2,28]]}}}