{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,31]],"date-time":"2026-01-31T05:16:43Z","timestamp":1769836603263,"version":"3.49.0"},"reference-count":91,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2021,4,17]],"date-time":"2021-04-17T00:00:00Z","timestamp":1618617600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"The Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico (CNPq), Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior (CAPES), Funda\u00e7\u00e3o de Apoio a Pesquisa do Estado de Santa Catarina (FAPESC), INCT-INOVAMED Program (),","award":["Grant 465430\/2014-7"],"award-info":[{"award-number":["Grant 465430\/2014-7"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Spirulina platensis is a \u201csuper-food\u201d and has attracted researchers\u2019 attention due to its anti-inflammatory, antioxidant, and analgesic properties. Herein, we investigated the antinociceptive effects of Spirulina in different rodent behavior models of inflammatory pain. Male Swiss mice were treated with Spirulina (3\u2013300 mg\/kg, p.o.), indomethacin (10 mg\/kg, p.o.), or vehicle (0.9% NaCl 10 mL\/kg). Behavioral tests were performed with administration of acetic acid (0.6%, i.p.), formalin 2.7% (formaldehyde 1%, i.pl.), menthol (1.2 \u00b5mol\/paw, i.pl.), cinnamaldehyde (10 nmol\/paw, i.pl.), capsaicin (1.6 \u00b5g\/paw, i.pl.), glutamate (20 \u00b5mol\/paw, i.pl.), or naloxone (1 mg\/kg, i.p.). The animals were also exposed to the rotarod and open field test to determine possible effects of Spirulina on locomotion and motor coordination. The quantitative phytochemical assays exhibited that Spirulina contains significant concentrations of total phenols and flavonoid contents, as well as it showed a powerful antioxidant effect with the highest scavenging activity. Oral administration of Spirulina completely inhibited the abdominal contortions induced by acetic acid (ED50 = 20.51 mg\/kg). Spirulina treatment showed significant inhibition of formalin-induced nociceptive behavior during the inflammatory phase, and the opioid-selective antagonist markedly blocked this effect. Furthermore, our data indicate that the mechanisms underlying Spirulina analgesia appear to be related to its ability to modulate TRMP8 and TRPA1, but not by TRPV1 or glutamatergic system. Spirulina represents an orally active and safe natural analgesic that exhibits great therapeutic potential for managing inflammatory pain disorders.<\/jats:p>","DOI":"10.3390\/biom11040592","type":"journal-article","created":{"date-parts":[[2021,4,18]],"date-time":"2021-04-18T22:15:13Z","timestamp":1618784113000},"page":"592","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":76,"title":["Involvement of Opioid System and TRPM8\/TRPA1 Channels in the Antinociceptive Effect of Spirulina platensis"],"prefix":"10.3390","volume":"11","author":[{"given":"Mariana A.","family":"Freitas","sequence":"first","affiliation":[{"name":"Laboratory of Autoimmunity and Immunopharmacology (LAIF), Department of Health Sciences, Campus Ararangu\u00e1, Universidade Federal de Santa Catarina, Ararangu\u00e1 88906-072, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amanda","family":"Vasconcelos","sequence":"additional","affiliation":[{"name":"Laboratory of Autoimmunity and Immunopharmacology (LAIF), Department of Health Sciences, Campus Ararangu\u00e1, Universidade Federal de Santa Catarina, Ararangu\u00e1 88906-072, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elaine C. D.","family":"Gon\u00e7alves","sequence":"additional","affiliation":[{"name":"Laboratory of Autoimmunity and Immunopharmacology (LAIF), Department of Health Sciences, Campus Ararangu\u00e1, Universidade Federal de Santa Catarina, Ararangu\u00e1 88906-072, Brazil"},{"name":"Post-Graduate Program of Neuroscience, Center of Biological Science, Campus Florian\u00f3polis, Universidade Federal de Santa Catarina, Florian\u00f3polis 88040-900, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eduarda G.","family":"Ferrarini","sequence":"additional","affiliation":[{"name":"Laboratory of Autoimmunity and Immunopharmacology (LAIF), Department of Health Sciences, Campus Ararangu\u00e1, Universidade Federal de Santa Catarina, Ararangu\u00e1 88906-072, Brazil"},{"name":"Post-Graduate Program of Neuroscience, Center of Biological Science, Campus Florian\u00f3polis, Universidade Federal de Santa Catarina, Florian\u00f3polis 88040-900, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gabriela B.","family":"Vieira","sequence":"additional","affiliation":[{"name":"Laboratory of Autoimmunity and Immunopharmacology (LAIF), Department of Health Sciences, Campus Ararangu\u00e1, Universidade Federal de Santa Catarina, Ararangu\u00e1 88906-072, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4054-0496","authenticated-orcid":false,"given":"Donatella","family":"Cicia","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Naples Federico II, 80131 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ma\u00edra","family":"Cola","sequence":"additional","affiliation":[{"name":"Laboratory of Autoimmunity and Immunopharmacology (LAIF), Department of Health Sciences, Campus Ararangu\u00e1, Universidade Federal de Santa Catarina, Ararangu\u00e1 88906-072, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3335-1822","authenticated-orcid":false,"given":"Raffaele","family":"Capasso","sequence":"additional","affiliation":[{"name":"Department of Agricultural Sciences, University of Naples Federico II, 80055 Portici, Italy"},{"name":"Endocannabinoid Research Group, 80078 Pozzuoli, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6938-2161","authenticated-orcid":false,"given":"Rafael C.","family":"Dutra","sequence":"additional","affiliation":[{"name":"Laboratory of Autoimmunity and Immunopharmacology (LAIF), Department of Health Sciences, Campus Ararangu\u00e1, Universidade Federal de Santa Catarina, Ararangu\u00e1 88906-072, Brazil"},{"name":"Post-Graduate Program of Neuroscience, Center of Biological Science, Campus Florian\u00f3polis, Universidade Federal de Santa Catarina, Florian\u00f3polis 88040-900, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,4,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2929","DOI":"10.2174\/0929867323666160615105746","article-title":"Functional foods and health effects: A nutritional biochemistry perspective","volume":"23","year":"2016","journal-title":"Curr. Med. Chem."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1038\/ejcn.2010.101","article-title":"Functional foods","volume":"64","author":"Henry","year":"2010","journal-title":"Eur. J. Clin. Nutr."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3772","DOI":"10.1093\/jn\/132.12.3772","article-title":"Functional foods: Benefits, concerns and challenges\u2014A position paper from the American Council on Science and Health","volume":"132","author":"Hasler","year":"2002","journal-title":"J. Nutr."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Hern\u00e1ndez-Lepe, M.A., Olivas-Aguirre, F.J., G\u00f3mez-Miranda, L.M., Hern\u00e1ndez-Torres, R.P., Manr\u00edquez-Torres, J.d.J., and Ramos-Jim\u00e9nez, A. (2019). Systematic physical exercise and Spirulina maxima supplementation improve body composition, cardiorespiratory fitness, and blood lipid profile: Correlations of a randomized double-blind controlled trial. Antioxidants, 8.","DOI":"10.3390\/antiox8110507"},{"key":"ref_5","first-page":"139","article-title":"Functional foods for augmenting nitric oxide activity and reducing the risk for salt-induced hypertension and cardiovascular disease in Japan","volume":"176","author":"Kurtz","year":"2019","journal-title":"J. Cardiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1080\/07315724.2017.1410867","article-title":"Functional food and cardiovascular disease prevention and treatment: A Review","volume":"37","author":"Asgary","year":"2018","journal-title":"J. Am. Coll. Nutr."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1155\/2018\/1459753","article-title":"Role of natural antioxidants from functional foods in neurodegenerative and metabolic disorders","volume":"2018","author":"Carvalho","year":"2018","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Konstantinidi, M., and Koutelidakis, A.E. (2019). Functional foods and bioactive compounds: A Review of its possible role on weight management and obesity\u2019s metabolic consequences. Medicines, 6.","DOI":"10.3390\/medicines6030094"},{"key":"ref_9","first-page":"305","article-title":"Graphic representation of the relationship between oxygen-consumption and characteristics of normal gait of the human male","volume":"75","author":"Serafini","year":"2016","journal-title":"Curr. Pharm. Des."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"M\u00e9rillon, J.-M., and Ramawat, K.G. (2018). Bioactive Molecules in Food, Springer.","DOI":"10.1007\/978-3-319-78030-6"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.copbio.2016.11.016","article-title":"Establishing health benefits of bioactive food components: A basic research scientist\u2019s perspective","volume":"44","author":"Yasmeen","year":"2017","journal-title":"Curr. Opin. Biotechnol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1016\/j.bbalip.2011.10.011","article-title":"Fish Oil and Plasma Triglycerides","volume":"23","author":"Shearer","year":"2012","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1016\/j.bbrc.2010.02.056","article-title":"PPAR\u03b3 regulates the expression of cholesterol metabolism genes in alveolar macrophages","volume":"393","author":"Baker","year":"2010","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Chiang, J.Y.L., and Li, T. (2009). Regulation of bile acid and cholesterol metabolism by PPARs. PPAR Res., 2009.","DOI":"10.1155\/2009\/501739"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Macia, L., Tan, J., Vieira, A.T., Leach, K., Stanley, D., Luong, S., Maruya, M., Ian McKenzie, C., Hijikata, A., and Wong, C. (2015). Metabolite-sensing receptors GPR43 and GPR109A facilitate dietary fibre-induced gut homeostasis through regulation of the inflammasome. Nat. Commun., 6.","DOI":"10.1038\/ncomms7734"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.foodres.2018.07.043","article-title":"Interplay between food and gut microbiota in health and disease","volume":"115","author":"Santos","year":"2019","journal-title":"Food Res. Int."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1038\/s41575-018-0054-1","article-title":"Inflammasomes in the gastrointestinal tract: Infection, cancer and gut microbiota homeostasis","volume":"15","author":"Man","year":"2018","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1017\/S0007114517000393","article-title":"Strawberry and cranberry polyphenols improve insulin sensitivity in insulin-resistant, non-diabetic adults: A parallel, double-blind, controlled and randomised clinical trial","volume":"117","author":"Paquette","year":"2017","journal-title":"Br. J. Nutr."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Alkhatib, A. (2020). Antiviral functional foods and exercise lifestyle prevention of coronavirus. Nutrients, 12.","DOI":"10.3390\/nu12092633"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1186\/s12906-017-1670-y","article-title":"The effects of Spirulina Platensis on anthropometric indices, appetite, lipid profile and serum vascular endothelial growth factor (VEGF) in obese individuals: A randomized double blinded placebo controlled trial","volume":"17","author":"Zeinalian","year":"2017","journal-title":"BMC Complement. Altern. Med."},{"key":"ref_21","first-page":"295","article-title":"Nutritional studies on Spirulina maxima","volume":"6","author":"Maranesi","year":"1984","journal-title":"Acta Vitaminol. Enzym."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"6382","DOI":"10.1038\/s41598-020-63272-5","article-title":"Spirulina platensis prevents oxidative stress and inflammation promoted by strength training in rats: Dose-response relation study","volume":"10","author":"Silva","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"279","DOI":"10.2174\/157340111804586457","article-title":"The Potential Health Benefits of Algae and Micro Algae in Medicine: A Review on Spirulina platensis","volume":"7","author":"Soheili","year":"2011","journal-title":"Curr. Nutr. Food Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1817","DOI":"10.1007\/s00204-016-1744-5","article-title":"The antioxidant, immunomodulatory, and anti-inflammatory activities of Spirulina: An overview","volume":"90","author":"Wu","year":"2016","journal-title":"Arch. Toxicol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2289","DOI":"10.2147\/JPR.S267347","article-title":"Oral spirulina platensis attenuates hyperglycemia and exhibits antinociceptive effect in streptozotocin-induced diabetic neuropathy rat model","volume":"13","author":"Ali","year":"2020","journal-title":"J. Pain Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1006\/bbrc.2000.3725","article-title":"Selective inhibition of cyclooxygenase-2 by C-phycocyanin, a biliprotein from Spirulina platensis","volume":"277","author":"Reddy","year":"2000","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3390","DOI":"10.1007\/s11064-017-2379-5","article-title":"Neuroprotective Activities of Spirulina platensis in the 6-OHDA Model of Parkinson\u2019s Disease Are Related to Its Anti-Inflammatory Effects","volume":"42","author":"Lima","year":"2017","journal-title":"Neurochem. Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1016\/j.jiph.2019.04.014","article-title":"Spirulina consumption effectively reduces anti-inflammatory and pain related infectious diseases","volume":"12","author":"Mohsen","year":"2019","journal-title":"J. Infect. Public Health"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"13525","DOI":"10.1073\/pnas.0705924104","article-title":"TRPA1 mediates formalin-induced pain","volume":"104","author":"McNamara","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"264","DOI":"10.19084\/RCA16011","article-title":"Uma abordagem sobre caracteriza\u00e7\u00e3o e avalia\u00e7\u00e3o do potencial antioxidante de extratos fen\u00f3licos de microalgas Spirulina sp. LEB-18 e Chlorella pyrenoidosa","volume":"40","author":"Machado","year":"2017","journal-title":"Rev. Ci\u00eancias Agr\u00e1rias"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"42","DOI":"10.53393\/rial.2009.v68.32741","article-title":"Compostos fen\u00f3licos totais, atividade antioxidante e antif\u00fangica de multimisturas enriquecidas com a microalga Spirulina platensis","volume":"68","author":"Machado","year":"2009","journal-title":"Rev. Inst. Adolfo Lutz"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Mokrani, A., and Madani, K. (2016). Effect of Solvent, Time and Temperature on the Extraction of Phenolic Compounds and Antioxidant Capacity of Peach (Prunus persica L.) Fruit, Elsevier.","DOI":"10.1016\/j.seppur.2016.01.043"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"144","DOI":"10.5344\/ajev.1965.16.3.144","article-title":"Colorimetry of total phenolics with phosphomolybdic-phosphotungstic acid reagents","volume":"16","author":"Singleton","year":"1965","journal-title":"Am. J. Enol. Vitic."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1016\/S0308-8146(98)00102-2","article-title":"The determination of flavonoid contents in mulberry and their scavenging effects on superoxide radicals","volume":"64","author":"Zhishen","year":"1999","journal-title":"Food Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"606","DOI":"10.3390\/ijms9040606","article-title":"Quantification of phenolic constituents and antioxidant activity of Pterodon emarginatus vogel seeds","volume":"9","author":"Dutra","year":"2008","journal-title":"Int. J. Mol. Sci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.1016\/S0891-5849(98)00315-3","article-title":"Antioxidant activity applying an improved abts radical cation decolorization assay","volume":"26","author":"Re","year":"1999","journal-title":"Free Radic. Biol. Med."},{"key":"ref_37","unstructured":"National Research Council (2011). Guide for the Care and Use of Laboratory Animals, The National Academic Press."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1055\/s-1999-13962","article-title":"Study of the antinociceptive action of the ethanolic extract and the triterpene 24-hydroxytormentic acid isolated from the stem bark of Ocotea suaveolens","volume":"65","author":"Beirith","year":"1999","journal-title":"Planta Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/S0304-3959(99)00008-1","article-title":"Differential effects of chemical and mechanical colonic irritation on behavioral pain response to intraperitoneal acetic acid in mice","volume":"81","author":"Coutinho","year":"1999","journal-title":"Pain"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/0304-3959(87)90088-1","article-title":"The formalin test in mice: Dissociation between inflammatory and non-inflammatory pain","volume":"30","author":"Hunskaar","year":"1987","journal-title":"Pain"},{"key":"ref_41","unstructured":"Broadhurst, P.L. (1960). Experiments in Psychogenetics, Routledge Kegan Paul."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1016\/j.neuro.2017.06.007","article-title":"Valproate and sodium butyrate attenuate manganese-decreased locomotor activity and astrocytic glutamate transporters expression in mice","volume":"64","author":"Johnson","year":"2018","journal-title":"Neurotoxicology"},{"key":"ref_43","unstructured":"Curzon, P., Zhang, M., Radek, R., and Fox, G. (2009). The behavioral assessment of sensorimotor processes in the mouse: Acoustic startle, sensory gating, locomotor activity, rotarod, and beam walking. Methods Behav. Anal. Neurosci., 2."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1016\/j.jep.2016.03.050","article-title":"Oral treatment with methanolic extract of the root bark of Condalia buxifolia Reissek alleviates acute pain and inflammation in mice: Potential interactions with PGE2, TRPV1\/ASIC and PKA signaling pathways","volume":"185","author":"Morel","year":"2016","journal-title":"J. Ethnopharmacol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1016\/j.jpain.2009.09.012","article-title":"The Nociception Induced by Glutamate in Mice Is Potentiated by Protons Released into the Solution","volume":"11","author":"Meotti","year":"2010","journal-title":"J. Pain"},{"key":"ref_46","first-page":"597","article-title":"Animal models of nociception","volume":"53","author":"Gozariu","year":"2001","journal-title":"Pharmacol. Rev."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.neuroscience.2011.12.041","article-title":"Tests and models of nociception and pain in rodents","volume":"211","author":"Barrot","year":"2012","journal-title":"Neuroscience"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1152\/jn.00524.2018","article-title":"Trpa1: A molecular view","volume":"121","author":"Meents","year":"2019","journal-title":"J. Neurophysiol."},{"key":"ref_49","unstructured":"Bernd, N., and Flockerzi, V. (2014). Mammalian Transient Receptor Potential (TRP) Cation Channels, Springer."},{"key":"ref_50","first-page":"48","article-title":"Termination of nociceptive bahaviour at the end of phase 2 of formalin test is attributable to endogenous inhibitory mechanisms, but not by opioid receptors activation","volume":"5","author":"Feridoni","year":"2014","journal-title":"Basic Clin. Neurosci."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.lfs.2014.02.031","article-title":"The contribution of transient receptor potential ankyrin 1 (TRPA1) to the in vivo nociceptive effects of prostaglandin E2","volume":"105","author":"Bonet","year":"2014","journal-title":"Life Sci."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"3397","DOI":"10.1111\/bph.13129","article-title":"The TRPA1 channel mediates the analgesic action of dipyrone and pyrazolone derivatives","volume":"172","author":"Nassini","year":"2015","journal-title":"Br. J. Pharmacol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1080\/10284150600929748","article-title":"Spirulina maxima pretreatment partially protects against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxicity","volume":"9","author":"Chamorro","year":"2006","journal-title":"Nutr. Neurosci."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"997","DOI":"10.1080\/14728222.2020.1815191","article-title":"TRPA1 as a therapeutic target for nociceptive pain","volume":"24","author":"Nassini","year":"2020","journal-title":"Expert Opin. Ther. Targets"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1007\/s12031-014-0472-7","article-title":"Effects of some natural carotenoids on TRPA1- and TRPV1-Induced neurogenic inflammatory processes in vivo in the mouse skin","volume":"56","author":"Deli","year":"2015","journal-title":"J. Mol. Neurosci."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1515\/jbcpp-2017-0042","article-title":"Evaluation of morning glory (Jacquemontia tamnifolia (L.) Griseb) leaves for antioxidant, antinociceptive, anticoagulant and cytotoxic activities","volume":"29","author":"Hossain","year":"2018","journal-title":"J. Basic Clin. Physiol. Pharmacol."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Djiazet, S., Kenfack, L.B.M., Devi, P.B., Nazareth, M.S., Tchi\u00e9gang, C., and Shetty, P.H. (2020). Phenolic profile, antioxidant and enzyme inhibitory activities of underutilized spices from Central Africa. J. Food Sci. Technol.","DOI":"10.1007\/s13197-020-04625-w"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1016\/j.foodchem.2019.01.037","article-title":"Recovery of phenolic antioxidants from Syrah grape pomace through the optimization of an enzymatic extraction process","volume":"283","author":"Meini","year":"2019","journal-title":"Food Chem."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1046\/j.1523-5408.2002.00004.x","article-title":"The role of carotenoids in human health","volume":"5","author":"Johnson","year":"2002","journal-title":"Nutr. Clin. Care"},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Park, W.S., Kim, H.J., Li, M., Lim, D.H., Kim, J., Kwak, S.S., Kang, C.M., Ferruzzi, M.G., and Ahn, M.J. (2018). Two classes of pigments, carotenoids and c-phycocyanin, in spirulina powder and their antioxidant activities. Molecules, 23.","DOI":"10.20944\/preprints201807.0470.v1"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1007\/s00210-014-0978-0","article-title":"Gallic acid functions as a TRPA1 antagonist with relevant antinociceptive and antiedematogenic effects in mice","volume":"387","author":"Trevisan","year":"2014","journal-title":"Naunyn. Schmiedebergs. Arch. Pharmacol."},{"key":"ref_62","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_63","doi-asserted-by":"crossref","first-page":"10999","DOI":"10.1038\/s41598-017-11194-0","article-title":"Novel selective, potent naphthyl TRPM8 antagonists identified through a combined ligand-and structure-based virtual screening approach","volume":"7","author":"Beccari","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_64","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_65","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_66","doi-asserted-by":"crossref","unstructured":"Julius, D. (2013). TRP Channels and Pain, CRC Press\/Taylor & Francis.","DOI":"10.1146\/annurev-cellbio-101011-155833"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1007\/978-94-007-0265-3_33","article-title":"Role of TRP channels in pain sensation","volume":"704","author":"Chung","year":"2011","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_68","first-page":"129","article-title":"Neuropathic Pain: A Clinical Perspective","volume":"16","author":"Baron","year":"2009","journal-title":"Handb. Exp. Pharmacol."},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Pereira, V., and Goudet, C. (2019). Emerging trends in pain modulation by metabotropic glutamate receptors. Front. Mol. Neurosci., 11.","DOI":"10.3389\/fnmol.2018.00464"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1323","DOI":"10.2174\/092986712799462630","article-title":"The Role of Glutamate Signaling in Pain Processes and its Regulation by GCP II Inhibition","volume":"19","author":"Wozniak","year":"2012","journal-title":"Curr. Med. Chem."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/j.neulet.2010.01.066","article-title":"Peripheral inhibition of glutaminase reduces carrageenan- induced Fos expression in the superficial dorsal horn of the rat Ernest","volume":"472","author":"Hoffman","year":"2010","journal-title":"Neurosci Lett."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1007\/s13238-016-0353-7","article-title":"Understand spiciness: Mechanism of TRPV1 channel activation by capsaicin","volume":"8","author":"Yang","year":"2017","journal-title":"Protein Cell"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"130","DOI":"10.2174\/138920111793937844","article-title":"TRPV1 Function in Health and Disease","volume":"12","author":"White","year":"2010","journal-title":"Curr. Pharm. Biotechnol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"392","DOI":"10.3389\/fphys.2017.00392","article-title":"TRPs in pain sensation","volume":"8","author":"Diez","year":"2017","journal-title":"Front. Physiol."},{"key":"ref_75","first-page":"435","article-title":"Antinociceptive effect of essential oils and their constituents: An update review","volume":"27","author":"Savegnago","year":"2016","journal-title":"J. Braz. Chem. Soc."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1856","DOI":"10.1097\/j.pain.0000000000001282","article-title":"Chronic neuropathic pain reduces opioid receptor availability with associated anhedonia in rat","volume":"159","author":"Thompson","year":"2018","journal-title":"Pain"},{"key":"ref_77","first-page":"5","article-title":"Opioid system modulates the immune function: A Review","volume":"1","author":"Liang","year":"2016","journal-title":"Transl. Perioper. Pain Med."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.jemermed.2018.04.022","article-title":"Naloxone use among emergency department patients with opioid overdose","volume":"55","author":"Marco","year":"2018","journal-title":"J. Emerg. Med."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"104083","DOI":"10.1016\/j.jff.2020.104083","article-title":"Beyond inflammation: centrally mediated antinociceptive properties of Spirulina platensis LEB-18 biomass via the opioid system","volume":"72","author":"Santos","year":"2020","journal-title":"J. Funct. Foods"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1007\/s10787-017-0356-x","article-title":"Quercetin inhibits gout arthritis in mice: Induction of an opioid-dependent regulation of inflammasome","volume":"25","author":"Mizokami","year":"2017","journal-title":"Inflammopharmacology"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"4442","DOI":"10.1073\/pnas.0914733107","article-title":"Morphine peripheral analgesia depends on activation of the PI3K\u03b3\/AKT\/nNOS\/NO\/KATP signaling pathway","volume":"107","author":"Cunha","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Tatem, K.S., Quinn, J.L., Phadke, A., Yu, Q., Gordish-Dressman, H., and Nagaraju, K. (2014). Behavioral and locomotor measurements using an open field activity monitoring system for skeletal muscle diseases. J. Vis. Exp., 51785.","DOI":"10.3791\/51785"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.seizure.2017.09.015","article-title":"Behavioral effects of antiepileptic drugs in rats: Are the effects on mood and behavior detectable in open-field test?","volume":"52","author":"Zimcikova","year":"2017","journal-title":"Seizure"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"561","DOI":"10.3389\/fphar.2017.00561","article-title":"PD-1 and PD-L1 checkpoint signaling inhibition for cancer immunotherapy: Mechanism, combinations, and clinical outcome","volume":"8","author":"Alsaab","year":"2017","journal-title":"Front. Pharmacol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"111513","DOI":"10.1016\/j.jphotobiol.2019.111513","article-title":"Photobiomodulation therapy reduces acute pain and inflammation in mice","volume":"196","author":"Pigatto","year":"2019","journal-title":"J. Photochem. Photobiol. B Biol."},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Souza, G.V., Simas, A.S., Bastos-Pereira, A.L., Frois, G.R.A., Ribas, J.L.C., Verdan, M.H., Kassuya, C.A.L., Stefanello, M.E., and Zampronio, A.R. (2015). Antinociceptive activity of the ethanolic extract, fractions, and aggregatin d isolated from sinningia aggregata Tubers. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0117501"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.cbi.2012.08.014","article-title":"Mechanism of interaction of novel uncharged, centrally active reactivators with OP-hAChE conjugates","volume":"203","author":"Sit","year":"2013","journal-title":"Chem. Biol. Interact."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.cbi.2018.04.003","article-title":"Antinociceptive activity of Riparin II from Aniba riparia: Further elucidation of the possible mechanisms","volume":"287","author":"Vasconcelos","year":"2018","journal-title":"Chem. Biol. Interact."},{"key":"ref_89","doi-asserted-by":"crossref","unstructured":"Nguelefack, T.B., Dutra, R.C., Paszcuk, A.F., de Andrade, E.L., and Calixto, J.B. (2015). TRPV1 channel inhibition contributes to the antinociceptive effects of Croton macrostachyus extract in mice. BMC Complement. Altern. Med., 15.","DOI":"10.1186\/s12906-015-0816-z"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.ijbiomac.2012.11.023","article-title":"Biological activities and potential health benefit effects of polysaccharides isolated from Lycium barbarum L","volume":"54","author":"Jin","year":"2013","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"375","DOI":"10.2147\/DMSO.S172104","article-title":"Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy Dovepress effects of Spirulina platensis microalgae on antioxidant and anti-inflammatory factors in diabetic rats","volume":"11","author":"Nasirian","year":"2018","journal-title":"Diabetes Metab. Syndr. Obes. Targets Ther."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/11\/4\/592\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:49:13Z","timestamp":1760161753000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/11\/4\/592"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,17]]},"references-count":91,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2021,4]]}},"alternative-id":["biom11040592"],"URL":"https:\/\/doi.org\/10.3390\/biom11040592","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,17]]}}}