{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T14:09:21Z","timestamp":1789740561664,"version":"4.0.1"},"reference-count":73,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2021,5,28]],"date-time":"2021-05-28T00:00:00Z","timestamp":1622160000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Vortioxetine is a multimodal antidepressant drug that affects several brain neurochemicals and has the potential to induce various pharmacological effects on the central nervous system. Therefore, we investigated the centrally mediated analgesic efficacy of this drug and the mechanisms underlying this effect. Analgesic activity of vortioxetine (5, 10 and 20 mg\/kg, p.o.) was examined by tail-clip, tail-immersion and hot-plate tests. Motor performance of animals was evaluated using Rota-rod device. Time course measurements (30\u2013180 min) showed that vortioxetine (10 and 20 mg\/kg) administrations significantly increased the response latency, percent maximum possible effect and area under the curve values in all of the nociceptive tests. These data pointed out the analgesic effect of vortioxetine on central pathways carrying acute thermal and mechanical nociceptive stimuli. Vortioxetine did not alter the motor coordination of mice indicating that the analgesic activity of this drug was specific. In mechanistic studies, pre-treatments with p-chlorophenylalanine (serotonin-synthesis inhibitor), NAN-190 (serotonin 5-HT1A receptor antagonist), \u03b1-methyl-para-tyrosine (catecholamine-synthesis inhibitor), phentolamine (non-selective \u03b1-adrenoceptor blocker), and naloxone (non-selective opioid receptor blocker) antagonised the vortioxetine-induced analgesia. Obtained findings indicated that vortioxetine-induced analgesia is mediated by 5-HT1A serotonergic, \u03b1-adrenergic and opioidergic receptors, and contributions of central serotonergic and catecholaminergic neurotransmissions are critical for this effect.<\/jats:p>","DOI":"10.3390\/molecules26113242","type":"journal-article","created":{"date-parts":[[2021,5,31]],"date-time":"2021-05-31T01:51:37Z","timestamp":1622425897000},"page":"3242","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["5-HT1A Serotonergic, \u03b1-Adrenergic and Opioidergic Receptors Mediate the Analgesic Efficacy of Vortioxetine in Mice"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0371-2703","authenticated-orcid":false,"given":"Nazl\u0131","family":"Turan Y\u00fccel","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Faculty of Pharmacy, Anadolu University, Eski\u015fehir 26470, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3314-1961","authenticated-orcid":false,"given":"\u00dcmm\u00fchan","family":"Kandemir","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Institute of Health Sciences, Anadolu University, Eski\u015fehir 26470, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00dcmide","family":"Demir \u00d6zkay","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Pharmacy, Anadolu University, Eski\u015fehir 26470, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00d6zg\u00fcr Devrim","family":"Can","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Pharmacy, Anadolu University, Eski\u015fehir 26470, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,5,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1007\/s40263-014-0195-x","article-title":"Vortioxetine: A review of its use in major depressive disorder","volume":"28","year":"2014","journal-title":"CNS Drugs"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.pharmthera.2014.07.001","article-title":"Vortioxetine, a novel antidepressant with multimodal activity: Review of preclinical and clinical data","volume":"145","author":"Sanchez","year":"2015","journal-title":"Pharm. Ther."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"666","DOI":"10.1124\/jpet.111.189068","article-title":"Pharmacological effects of Lu AA21004: A novel multimodal compound for the treatment of major depressive disorder","volume":"340","author":"Pehrson","year":"2012","journal-title":"J. Pharm. Exp. Ther."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/j.euroneuro.2012.04.006","article-title":"Lu AA21004, a novel multimodal antidepressant, produces regionally selective increases of multiple neurotransmitters-a rat microdialysis and electrophysiology study","volume":"23","author":"Pehrson","year":"2013","journal-title":"Eur. Neuropsychopharmacol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1016\/S0924-977X(08)70440-1","article-title":"Lu AA21004: A novel potential treatment for mood disorders","volume":"18","author":"Moore","year":"2008","journal-title":"Eur. Neuropsychopharmacol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.pbb.2013.01.019","article-title":"Vortioxetine (Lu AA21004), a novel multimodal antidepressant, enhances memory in rats","volume":"105","author":"Montezinho","year":"2013","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1016\/S0924-977X(13)70301-8","article-title":"Vortioxetine, a novel multimodal antidepressant, modulates GABA and glutamate neurotransmission via serotonergic mechanisms","volume":"23","author":"Pehrson","year":"2013","journal-title":"Eur. Neuropsychopharmacol."},{"key":"ref_8","first-page":"557","article-title":"Protective effects of vortioxetine in predator scent stress model of post-traumatic stress disorder in rats: Role on neuroplasticity and apoptosis","volume":"70","author":"Ozbeyli","year":"2019","journal-title":"J. Physiol. Pharm."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12991-018-0190-6","article-title":"An open-label, flexible dose adaptive study evaluating the efficacy of vortioxetine in subjects with panic disorder","volume":"17","author":"Shah","year":"2018","journal-title":"Ann. Gen. Psychiatry"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1590\/0004-282x20190064","article-title":"The effect of vortioxetine on penicillin-induced epileptiform activity in rats","volume":"77","year":"2019","journal-title":"Arq. Neuropsiquiatr."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1017\/S1461145708008766","article-title":"Role of serotonin 5-HT1A receptors in the antidepressant-like effect and the antinociceptive effect of venlafaxine in mice","volume":"12","author":"Berrocoso","year":"2009","journal-title":"Int. J. Neuropsychopharmacol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1016\/j.neuropharm.2004.09.012","article-title":"Antinociceptive effects of the antidepressants amitriptyline, duloxetine, mirtazapine and citalopram in animal models of acute, persistent and neuropathic pain","volume":"48","author":"Bomholt","year":"2005","journal-title":"Neuropharmacology"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/0160-5402(91)90063-B","article-title":"A revised rotarod procedure for measuring the effect of antinociceptive drugs on motor function in the rat","volume":"6","author":"Cartmell","year":"1991","journal-title":"J. Pharmacol. Methods"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.lfs.2016.08.031","article-title":"Opioid system mediated anti-nociceptive effect of agomelatine in mice","volume":"15","author":"Kasap","year":"2016","journal-title":"Life Sci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/j.neuropharm.2013.05.014","article-title":"Antidepressant and anxiolytic potential of the multimodal antidepressant vortioxetine (Lu AA21004) assessed by behavioural and neurogenesis outcomes in mice","volume":"73","author":"Guilloux","year":"2013","journal-title":"Neuropharmacology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1177\/1744806918808987","article-title":"Multimodal antidepressant vortioxetine causes analgesia in a mouse model of chronic neuropathic pain","volume":"14","author":"Zuena","year":"2018","journal-title":"Mol. Pain"},{"key":"ref_17","first-page":"597","article-title":"Animal models of nociception","volume":"53","author":"Gozariu","year":"2001","journal-title":"Pharmacol. Rev."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fphar.2018.00085","article-title":"Polymethoxyflavones from Nicotiana plumbaginifolia (Solanaceae) exert antinociceptive and neuropharmacological effects in mice","volume":"9","author":"Shajib","year":"2018","journal-title":"Front. Pharmacol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"109975","DOI":"10.1016\/j.pnpbp.2020.109975","article-title":"Vortioxetine reduces pain hypersensitivity and associated depression-like behavior in mice with oxaliplatin-induced neuropathy","volume":"103","author":"Micov","year":"2020","journal-title":"Prog. Neuropsychopharmacol. Biol. Psychiatry"},{"key":"ref_20","unstructured":"Bang-Andersen, B., Faldt, A., Moerk, A., Lopez De Diego, H., Holm, R., Stensboel, T.B., Ringgaard, L.M., Mealy, M.J., Rock, M.H., and Brodersen, J. (2007). 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl] Piperazine as a Compound with Combined Serotonin Reuptake, 5-HT3 and 5-HT1A Activity for the Treatment of Cognitive Impairment. (WO 2007\/144005 A1)."},{"key":"ref_21","unstructured":"Moore, N., and Stensboel, T.B. (2008). 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl] Piperazine as a Compound with Combined Serotonin Reuptake, 5-HT3 and 5-HT1A Activity for the Treatment of Pain or Residual Symptoms in Depression Relating to Sleep and Cognition. (WO 2008\/113359 A2)."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1097\/00044067-200507000-00003","article-title":"The endogenous opioid system and clinical pain management","volume":"16","author":"Holden","year":"2005","journal-title":"AACN Clin. Issues"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1016\/S0301-0082(02)00009-6","article-title":"Descending control of pain","volume":"66","author":"Millan","year":"2002","journal-title":"Prog. Neurobiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1016\/0091-3057(85)90537-4","article-title":"Pharmacology of spinal adrenergic systems which modulate spinal nociceptive processing","volume":"22","author":"Yaksh","year":"1985","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_25","first-page":"499","article-title":"p-Chlorophenylalanine: A specific depletor of brain serotonin","volume":"154","author":"Koe","year":"1996","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_26","first-page":"462","article-title":"Serotonin in pain and pain control","volume":"Volume 21","author":"Jacobs","year":"2010","journal-title":"Handbook of Behavioral Neurobiology of Serotonin"},{"key":"ref_27","first-page":"210","article-title":"Review: 5-HT1, 5-HT2, 5-HT3 and 5-HT7 receptors and their role in the modulation of pain response in the central nervous system","volume":"16","author":"Jaime","year":"2018","journal-title":"Curr. Neuropharmacol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/0006-8993(91)90400-P","article-title":"Autoradiographic mapping of 5-HT1, 5-HT1A, 5-HT1B and 5-HT2 receptors in the rat spinal cord","volume":"550","author":"Marlier","year":"1991","journal-title":"Brain Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/0304-3940(87)90218-7","article-title":"Autoradiographic evidence of serotonin 1 binding sites on primary afferent fibers in the dorsal horn of the rat spinal cord","volume":"83","author":"Daval","year":"1987","journal-title":"Neurosci. Lett."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1956","DOI":"10.1111\/j.1476-5381.2011.01685.x","article-title":"Role of 5-HT1 receptor subtypes in the modulation of pain and synaptic transmission in rat spinal superficial dorsal horn","volume":"165","author":"Jeong","year":"2012","journal-title":"Br. J. Pharm."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1093\/bja\/88.5.679","article-title":"Antinociceptive role of 5-HT1A receptors in rat spinal cord","volume":"88","author":"Nadeson","year":"2002","journal-title":"Br. J. Anaesth."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/S0014-2999(96)00819-9","article-title":"The effect of 5-HTIA receptor stimulation on nociceptive dorsal horn neurones in rats","volume":"318","author":"Gjerstad","year":"1996","journal-title":"Eur. J. Pharm."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/0006-8993(90)90025-7","article-title":"The role of spinal cord 5-HT1A and 5-HT1B receptors in the modulation of a spinal nociceptive reflex","volume":"536","author":"Eide","year":"1990","journal-title":"Brain Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.brainres.2018.03.016","article-title":"NLX-112, a highly selective 5-HT 1A receptor agonist, mediates analgesia and antidepressant-like activity in rats via spinal cord and prefrontal cortex 5-HT 1A receptors, respectively","volume":"1688","author":"Bardin","year":"2018","journal-title":"Brain Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/j.neuropharm.2017.07.022","article-title":"Antinociceptive, antiallodynic and antihyperalgesic effects of the 5-HT1A receptor selective agonist, NLX-112 in mouse models of pain","volume":"125","author":"Rojek","year":"2017","journal-title":"Neuropharmacology"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"7851","DOI":"10.1021\/jm400766k","article-title":"New serotonin 5-HT1A receptor agonists endowed with antinociceptive activity in vivo","volume":"56","author":"Valhondo","year":"2013","journal-title":"J. Med. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1159\/000068404","article-title":"Profound, non-opioid analgesia produced by the high-efficacy 5-HT(1A) agonist F 13640 in the formalin model of tonic nociceptive pain","volume":"67","author":"Bardin","year":"2003","journal-title":"Pharmacology"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1016\/0304-3959(92)90042-A","article-title":"Putative mechanisms of buspirone-induced antinociception in the rat","volume":"50","author":"Giordano","year":"1992","journal-title":"Pain"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1007\/BF00495547","article-title":"Inhibition of the in vivo biosynthesis and changes of catecholamine levels in rat brain after alpha-methyl-p-tyrosine; time- and dose\u2013response relationships","volume":"304","author":"Lewander","year":"1978","journal-title":"Naunyn Schmiedebergs Arch. Pharm."},{"key":"ref_40","first-page":"1101","article-title":"Antidepressant-like behavioral effects in 5-hydroxytryptamine (1A) and 5-hydroxytryptamine (1B) receptor mutant mice","volume":"298","author":"Mayorga","year":"2001","journal-title":"J. Pharm. Exp. Ther."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1097\/00000542-200002000-00030","article-title":"Norepinephrine facilitates inhibitory transmission in substantia gehtinosa of adult rat spinal cord (Part 1): Effects on axon terminals of GABAergic and glycinergic neurons","volume":"92","author":"Baba","year":"2000","journal-title":"Anesthesiology"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1254\/jjp.86.423","article-title":"Involvement of \u03b22-adrenergic and \u00b5-opioid receptors in antinociception produced by intracerebroventricular administration of \u03b1, \u03b2-methylene-ATP","volume":"86","author":"Fukui","year":"2001","journal-title":"Jpn. J. Pharm."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.pneurobio.2006.08.001","article-title":"Noradrenergic pain modulation","volume":"80","author":"Pertovaara","year":"2006","journal-title":"Prog. Neurobiol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1113\/jphysiol.2003.054932","article-title":"Actions of noradrenaline on substantia gelatinosa neurones in the rat spinal cord revealed by in vivo patch recording","volume":"555","author":"Sonohata","year":"2004","journal-title":"J. Physiol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1016\/j.ejphar.2017.09.018","article-title":"Antinociception induced by a novel \u03b12A adrenergic receptor agonist in rodents acute and chronic pain models","volume":"815","author":"Sudo","year":"2017","journal-title":"Eur. J. Pharm."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1111\/bph.12695","article-title":"Analgesic synergy between opioid and \u03b12-adrenoceptors","volume":"172","author":"Schuster","year":"2015","journal-title":"Br. J. Pharm."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1038\/nrn1431","article-title":"State-dependent opioid control of pain","volume":"5","author":"Fields","year":"2004","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"14519","DOI":"10.1073\/pnas.0705740104","article-title":"Central serotonergic neurons are differentially required for opioid analgesia but not for morphine tolerance or morphine reward","volume":"104","author":"Zhao","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_49","unstructured":"Hardman, J.G., Limbird, L.E., and Gilman, A.G. (2001). Catecholamines, symapthomimetic drugs, and adrenergic receptor antagonists. Goodman & Gilman\u2019s The Pharmacological Basis of Therapeutics, McGraw-Hill. [10th ed.]."},{"key":"ref_50","unstructured":"Hemmings, H.C., and Egan, T.D. (2019). Antihypertensive drugs and vasodilators. Pharmacology and Physiology for Anesthesia Foundations and Clinical Application, Saunders. [2nd ed.]."},{"key":"ref_51","unstructured":"Enna, S.J., and Bylund, D.B. (2008). Phentolamine. xPharm: The Comprehensive Pharmacology Reference, Elsevier. [1st ed.]."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Vardanyan, R., and Hruby, V. (2016). Drugs for treatment of erectile dysfunction. Synthesis of Best-Seller Drugs, Academic Press. [1st ed.].","DOI":"10.1016\/B978-0-12-411492-0.00038-9"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1097\/WNR.0b013e3283232caa","article-title":"5-HT antagonists NAN-190 and SB 269970 block alpha2-adrenoceptors in the guinea pig","volume":"20","author":"Foong","year":"2009","journal-title":"Neuroreport"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1210\/endo.133.1.8391422","article-title":"Serotonergic inhibition of rat Leydig cell function by propranolol","volume":"133","author":"Tinajero","year":"1993","journal-title":"Endocrinology"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.pbb.2013.04.014","article-title":"Anti-nociceptive effect of vitexin mediated by the opioid system in mice","volume":"109","author":"Can","year":"2013","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1111\/j.1472-8206.2011.00987.x","article-title":"Opioid-like antinociceptive effects of oral administration of a lectin purified from the seeds of Canavalia brasiliensis","volume":"27","author":"Assreuy","year":"2013","journal-title":"Fundam. Clin. Pharm."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1248\/bpb.33.209","article-title":"Assessment of mechanisms involved in antinociception caused by myrsinoic acid B","volume":"33","author":"Hess","year":"2010","journal-title":"Biol. Pharm. Bull."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"872","DOI":"10.1016\/j.jep.2012.03.043","article-title":"Involvement of 5-HT1A in the anxiolytic-like effect of dichloromethane fraction of Pimenta pseudocaryophyllus","volume":"141","author":"Fajemiroye","year":"2012","journal-title":"J. Ethnopharmacol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/j.lfs.2017.09.023","article-title":"Antidepressant-like effect of gallic acid in mice: Dual involvement of serotonergic and catecholaminergic systems","volume":"190","author":"Can","year":"2017","journal-title":"Life Sci."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1016\/j.euroneuro.2009.06.004","article-title":"The antinociceptive properties of reboxetine in acute pain","volume":"19","author":"Schreiber","year":"2009","journal-title":"Eur. Neuropsychopharmacol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/S0166-4328(00)00185-6","article-title":"The antinociceptive effect of trazodone in mice is mediated through both mu-opioid and serotonergic mechanisms","volume":"114","author":"Schreiber","year":"2000","journal-title":"Behav. Brain Res."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/S0304-3940(99)00627-8","article-title":"The antinociceptive effect of venlafaxine in mice is mediated through opioid and adrenergic mechanisms","volume":"273","author":"Schreiber","year":"1999","journal-title":"Neurosci. Lett."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1111\/j.1476-5381.1983.tb10499.x","article-title":"Antinociceptive properties of thyrotropin releasing hormone in mice: Comparison with morphine","volume":"79","author":"Boschi","year":"1983","journal-title":"Br. J. Pharm."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1159\/000088211","article-title":"Pharmacological investigation of trimetazidine in models of inflammation, pain and gastric injury in rodents","volume":"75","year":"2005","journal-title":"Pharmacology"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"309","DOI":"10.2174\/1871527317666180420150249","article-title":"Monoamine involvement in the antidepressant-like effect of \u03b2-caryophyllene","volume":"17","author":"Florentino","year":"2018","journal-title":"CNS Neurol. Disord. Drug Targets"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1043","DOI":"10.3389\/fnins.2018.01043","article-title":"GABA and 5-HT systems are involved in the anxiolytic effect of Gan-Mai-Da-Zao decoction","volume":"12","author":"Chen","year":"2019","journal-title":"Front. Neurosci."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1016\/j.neuropharm.2005.01.012","article-title":"Mechanisms involved in the antinociception caused by agmatine in mice","volume":"248","author":"Santos","year":"2005","journal-title":"Neuropharmacology"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1007\/PL00005094","article-title":"Caffeine induces central cholinergic analgesia","volume":"356","author":"Ghelardini","year":"1997","journal-title":"Naunyn Schmiedebergs Arch. Pharm."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1002\/jps.3030460322","article-title":"A note on a simple apparatus for detecting neurological deficit in rats and mice","volume":"46","author":"Dunham","year":"1957","journal-title":"J. Am. Pharm. Assoc."},{"key":"ref_70","first-page":"300","article-title":"The evaluation of analgesic action of pethidine hydrochloride (Demerol)","volume":"80","author":"Woolfe","year":"1944","journal-title":"J. Pharm. Exp. Ther."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"2019","DOI":"10.1185\/03007995.2011.614934","article-title":"Mechanisms of pain transmission and pharmacologic management","volume":"27","author":"Argoff","year":"2011","journal-title":"Curr. Med. Res. Opin."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1324","DOI":"10.1056\/NEJMoa042580","article-title":"Morphine, gabapentin, or their combination for neuropathic pain","volume":"352","author":"Gilron","year":"2005","journal-title":"N. Engl. J. Med."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1S12","DOI":"10.1016\/S0013-7006(16)30015-X","article-title":"Pharmacological properties of vortioxetine and its pre-clinical consequences","volume":"42","author":"David","year":"2016","journal-title":"Encephale"}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/26\/11\/3242\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:09:34Z","timestamp":1760162974000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/26\/11\/3242"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,28]]},"references-count":73,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2021,6]]}},"alternative-id":["molecules26113242"],"URL":"https:\/\/doi.org\/10.3390\/molecules26113242","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,28]]}}}