{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T18:25:29Z","timestamp":1782930329617,"version":"3.54.5"},"reference-count":46,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2022,8,24]],"date-time":"2022-08-24T00:00:00Z","timestamp":1661299200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003827","name":"National Research, Development, and Innovation Fund of Hungary","doi-asserted-by":"publisher","award":["2018-1.3.1-VKE-2018-00030"],"award-info":[{"award-number":["2018-1.3.1-VKE-2018-00030"]}],"id":[{"id":"10.13039\/501100003827","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Current treatment approaches to manage neuropathic pain have a slow onset and their use is largely hampered by side-effects, thus there is a significant need for finding new medications. Tolperisone, a centrally acting muscle relaxant with a favorable side effect profile, has been reported to affect ion channels, which are targets for current first-line medications in neuropathic pain. Our aim was to explore its antinociceptive potency in rats developing neuropathic pain evoked by partial sciatic nerve ligation and the mechanisms involved. Acute oral tolperisone restores both the decreased paw pressure threshold and the elevated glutamate level in cerebrospinal fluid in neuropathic rats. These effects were comparable to those of pregabalin, a first-line medication in neuropathy. Tolperisone also inhibits release of glutamate from rat brain synaptosomes primarily by blockade of voltage-dependent sodium channels, although inhibition of calcium channels may also be involved at higher concentrations. However, pregabalin fails to affect glutamate release under our present conditions, indicating a different mechanism of action. These results lay the foundation of the avenue for repurposing tolperisone as an analgesic drug to relieve neuropathic pain.<\/jats:p>","DOI":"10.3390\/ijms23179564","type":"journal-article","created":{"date-parts":[[2022,8,24]],"date-time":"2022-08-24T21:03:51Z","timestamp":1661375031000},"page":"9564","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["The Acute Antiallodynic Effect of Tolperisone in Rat Neuropathic Pain and Evaluation of Its Mechanism of Action"],"prefix":"10.3390","volume":"23","author":[{"given":"P\u00e9ter P.","family":"Lakatos","sequence":"first","affiliation":[{"name":"Department of Pharmacodynamics, Semmelweis University, 4 Nagyv\u00e1rad t\u00e9r, H-1089 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3159-6292","authenticated-orcid":false,"given":"D\u00e1vid \u00c1rp\u00e1d","family":"Kar\u00e1di","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Pharmacotherapy, Semmelweis University, 4 Nagyv\u00e1rad t\u00e9r, H-1089 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna Rita","family":"Galambos","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Pharmacotherapy, Semmelweis University, 4 Nagyv\u00e1rad t\u00e9r, H-1089 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nariman","family":"Essmat","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Pharmacotherapy, Semmelweis University, 4 Nagyv\u00e1rad t\u00e9r, H-1089 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Korn\u00e9l","family":"Kir\u00e1ly","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Pharmacotherapy, Semmelweis University, 4 Nagyv\u00e1rad t\u00e9r, H-1089 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rudolf","family":"Laufer","sequence":"additional","affiliation":[{"name":"Department of Pharmacodynamics, Semmelweis University, 4 Nagyv\u00e1rad t\u00e9r, H-1089 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8085-816X","authenticated-orcid":false,"given":"Orsolya","family":"Geda","sequence":"additional","affiliation":[{"name":"Department of Pharmacodynamics, Semmelweis University, 4 Nagyv\u00e1rad t\u00e9r, H-1089 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7312-618X","authenticated-orcid":false,"given":"Zolt\u00e1n S.","family":"Z\u00e1dori","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Pharmacotherapy, Semmelweis University, 4 Nagyv\u00e1rad t\u00e9r, H-1089 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5343-0205","authenticated-orcid":false,"given":"Tam\u00e1s","family":"T\u00e1bi","sequence":"additional","affiliation":[{"name":"Department of Pharmacodynamics, Semmelweis University, 4 Nagyv\u00e1rad t\u00e9r, H-1089 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8488-3266","authenticated-orcid":false,"given":"Mahmoud","family":"Al-Khrasani","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Pharmacotherapy, Semmelweis University, 4 Nagyv\u00e1rad t\u00e9r, H-1089 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00c9va","family":"Sz\u00f6k\u0151","sequence":"additional","affiliation":[{"name":"Department of Pharmacodynamics, Semmelweis University, 4 Nagyv\u00e1rad t\u00e9r, H-1089 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e12137","DOI":"10.1111\/jabr.12137","article-title":"The neurobiology of central sensitization","volume":"23","author":"Harte","year":"2018","journal-title":"J. Appl. Biobehav. Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/j.brainresbull.2019.07.008","article-title":"Glycine transporter inhibitors: A new avenue for managing neuropathic pain","volume":"152","author":"Mohammadzadeh","year":"2019","journal-title":"Brain Res. Bull."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1016\/0361-9230(93)90278-J","article-title":"Glutamate Immunocytochemistry in the Dorsal Horn After Injury or Stimulation of the Sciatic Nerve of Rats","volume":"30","author":"Weinberg","year":"1993","journal-title":"Res. Bull."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1113\/expphysiol.2012.069922","article-title":"The Glutamatergic System as a Target for Neuropathic Pain Relief","volume":"98","author":"Osikowicz","year":"2012","journal-title":"Exp. Physiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1002\/ana.22485","article-title":"Gain of function Nanu1.7 mutations in idiopathic small fiber neuropathy","volume":"71","author":"Faber","year":"2012","journal-title":"Ann. Neurol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1868","DOI":"10.1523\/JNEUROSCI.21-06-01868.2001","article-title":"Upregulation of Dorsal Root Ganglion Alpha2Delta Calcium Channel Subunit and Its Correlation with Allodynia in Spinal Nerve-injured Rats","volume":"21","author":"Luo","year":"2001","journal-title":"J. Neurosci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"17002","DOI":"10.1038\/nrdp.2017.2","article-title":"Neuropathic pain","volume":"3","author":"Colloca","year":"2017","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"970","DOI":"10.1111\/j.1476-5381.2012.02082.x","article-title":"Targeting voltage-gated calcium channels: Developments in peptide and small-molecule inhibitors for the treatment of neuropathic pain","volume":"167","author":"Vink","year":"2012","journal-title":"Br. J. Pharm."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1002\/(SICI)1097-4598(199904)22:4<502::AID-MUS12>3.0.CO;2-K","article-title":"Channels in Dorsal Root Ganglion Neurons Following Axotomy","volume":"22","author":"Ishikawa","year":"1999","journal-title":"Muscle Nerve"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Mohammadzadeh, A., Lakatos, P.P., Balogh, M., Zador, F., Karadi, D.A., Zadori, Z.S., Kiraly, K., Galambos, A.R., Barsi, S., and Riba, P. (2021). Pharmacological Evidence on Augmented Antiallodynia Following Systemic Co-Treatment with GlyT-1 and GlyT-2 Inhibitors in Rat Neuropathic Pain Model. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22052479"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1002\/tcr.20145","article-title":"Glutamate transporter blockers for elucidation of the function of excitatory neurotransmission systems","volume":"8","author":"Shimamoto","year":"2008","journal-title":"Chem. Rec."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1016\/0304-3959(96)03187-9","article-title":"Efficacy and Tolerance of Repeated Oral Doses of Tolperisone Hydrochloride in the Treatment of Painful Reflex Muscle Spasm: Results of a Prospective Placebo-controlled Double-blind Trial","volume":"67","author":"Pratzel","year":"1996","journal-title":"Pain"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/j.ejphar.2006.03.034","article-title":"A comparative study of the action of tolperisone on seven different voltage dependent sodium channel isoforms","volume":"538","author":"Hofer","year":"2006","journal-title":"Eur. J. Pharmacol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.neulet.2003.08.029","article-title":"No blocking effects of the pentapeptide QYNAD on Na+ channel subtypes expressed in Xenopus oocytes or action potential conduction in isolated rat sural nerve","volume":"352","author":"Quasthoff","year":"2003","journal-title":"Neurosci. Lett."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1016\/0014-2999(89)90791-7","article-title":"Suppression of Calcium Current ina Snail Neurone by Eperisone and Its Analogues","volume":"168","author":"Sun","year":"1989","journal-title":"Eur. J. Pharm."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1146\/annurev.pharmtox.44.101802.121627","article-title":"Voltage-gated sodium channels and hyperalgesia","volume":"44","author":"Lai","year":"2004","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1113-e88","DOI":"10.1111\/j.1468-1331.2010.02999.x","article-title":"EFNS guidelines on the pharmacological treatment of neuropathic pain: 2010 revision","volume":"17","author":"Attal","year":"2010","journal-title":"Eur. J. Neurol."},{"key":"ref_18","first-page":"1","article-title":"Models of Neuropathic Pain in the Rat","volume":"5","author":"Bennett","year":"2003","journal-title":"Curr. Protoc. Pharmacol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1413","DOI":"10.1016\/0306-4522(80)90002-0","article-title":"Aminopyridines and Synaptic Transmission","volume":"5","author":"Thesleff","year":"1980","journal-title":"Neuroscience"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/0166-2236(96)10031-X","article-title":"Presynaptic Receptors and the Control of Glutamate Exocytosis","volume":"19","author":"Budd","year":"1996","journal-title":"Trends Neurosci."},{"key":"ref_21","first-page":"346","article-title":"Characterization of Presynaptic Calcium Channels with w-Conotoxin MVIIC and w-Grammotoxin SIA: Role for a Resistant Calcium Channel Type in Neurosecretion","volume":"47","author":"Turner","year":"1995","journal-title":"Mol. Pharmacol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1038\/sj.bjp.0702574","article-title":"The Effects of Verapamil and Diltiazem on N-, P- and Q-type Calcium Channels Mediating Dopamine Release in Rat Striatum","volume":"127","author":"Dobrev","year":"1999","journal-title":"Br. J. Pharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1002\/syn.10094","article-title":"Preferential action of gabapentin and pregabalin at P\/Q-type voltage-sensitive calcium channels: Inhibition of K+-evoked [3H]-norepinephrine release from rat neocortical slices","volume":"45","author":"Dooley","year":"2002","journal-title":"Synapse"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1016\/j.brainres.2005.08.043","article-title":"Depolarization-induced release of ethanolamine from brain synaptic preparations in vitro","volume":"1060","author":"Liao","year":"2005","journal-title":"Brain Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1908999","DOI":"10.1002\/adfm.201908999","article-title":"Neuromodulation Management of Chronic Neuropathic Pain in The Central Nervous system","volume":"30","author":"Yu","year":"2020","journal-title":"Adv. Funct. Mater."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"S2","DOI":"10.1093\/pm\/pnz075","article-title":"A Comprehensive Algorithm for Management of Neuropathic Pain","volume":"20","author":"Bates","year":"2019","journal-title":"Pain Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1016\/0304-3959(90)91074-S","article-title":"A Novel Behavioral Model of Neuropathic Pain Disorders Produced in Rats by Partial Sciatic Nerve Injury","volume":"43","author":"Seltzer","year":"1990","journal-title":"Pain"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Fernandez-Montoya, J., Avendano, C., and Negredo, P. (2017). The Glutamatergic System in Primary Somatosensory Neurons and Its Involvement in Sensory Input-Dependent Plasticity. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19010069"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1097\/ALN.0000000000002130","article-title":"Neuroinflammation and Central Sensitization in Chronic and Widespread Pain","volume":"129","author":"Ji","year":"2018","journal-title":"Anesthesiology"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2422","DOI":"10.1016\/j.pain.2012.08.011","article-title":"Peripheral nerve injury produces a sustained shift in the balance between glutamate release and uptake in the dorsal horn of the spinal cord","volume":"153","author":"Inquimbert","year":"2012","journal-title":"Pain"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2570","DOI":"10.1152\/jn.00013.2010","article-title":"Impaired glial glutamate uptake induces extrasynaptic glutamate spillover in the spinal sensory synapses of neuropathic rats","volume":"103","author":"Nie","year":"2010","journal-title":"J. Neurophysiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/j.pain.2006.12.020","article-title":"Altered Spinal Arachidonic Acid Turnover After Peripheral Nerve Injury Regulates Regional Glutamate Concentration and Neuropathic Pain Behaviors in Rats","volume":"132","author":"Sung","year":"2007","journal-title":"Pain"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"53","DOI":"10.3389\/fphar.2019.00053","article-title":"LPM580098, a Novel Triple Reuptake Inhibitor of Serotonin, Noradrenaline and Dopamine, Attenuates Neuropathic Pain","volume":"10","author":"Li","year":"2019","journal-title":"Front. Pharmacol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.pbb.2015.11.008","article-title":"Spontaneous and evoked pain-associated behaviors in a rat model of neuropathic pain respond differently to drugs with different mechanisms of action","volume":"141","author":"Murai","year":"2016","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Murphy, K.M. (2018). Synaptosomes, Springer.","DOI":"10.1007\/978-1-4939-8739-9"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1007\/978-1-4939-8739-9_7","article-title":"Synaptosomal Bioenergetics and Glutamate Release","volume":"Volume 141","author":"Murphy","year":"2018","journal-title":"Synaptosomes"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/5584_2018_326","article-title":"Lidocaine, a Non-selective Inhibitor of Voltage-Gated Sodium Channels, Blocks Chemically-Induced Cough in Awake Naive Guinea Pigs","volume":"1160","author":"Svajdova","year":"2019","journal-title":"Adv. Exp. Med. Biol"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1007\/s00210-011-0620-3","article-title":"Effects of antiepileptic drugs on glutamate release from rat and human neocortical synaptosomes","volume":"383","author":"Kammerer","year":"2011","journal-title":"Naunyn-Schmiedeberg\u2019s Arch. Pharmacol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"4076","DOI":"10.1523\/JNEUROSCI.0356-09.2009","article-title":"The increased trafficking of the calcium channel subunit alpha2delta-1 to presynaptic terminals in neuropathic pain is inhibited by the alpha2delta ligand pregabalin","volume":"29","author":"Bauer","year":"2009","journal-title":"J. Neurosci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/j.brainresbull.2019.02.001","article-title":"Similarity and dissimilarity in antinociceptive effects of dipeptidyl-peptidase 4 inhibitors, Diprotin A and vildagliptin in rat inflammatory pain models following spinal administration","volume":"147","author":"Balogh","year":"2019","journal-title":"Brain Res. Bull."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"690","DOI":"10.1002\/j.1532-2149.2011.00070.x","article-title":"Relative contributions of peripheral versus supraspinal or spinal opioid receptors to the antinociception of systemic opioids","volume":"16","author":"Khalefa","year":"2012","journal-title":"Eur. J. Pain"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1093\/brain\/awl330","article-title":"Nerve growth factor governs the enhanced ability of opioids to suppress inflammatory pain","volume":"130","author":"Mousa","year":"2007","journal-title":"Brain"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1007\/s00210-002-0563-9","article-title":"Pharmacological characterisation of the somatostatin analogue TT-232: Effects on neurogenic and non-neurogenic inflammation and neuropathic hyperalgesia","volume":"366","author":"Pinter","year":"2002","journal-title":"Naunyn-Schmiedeberg\u2019s Arch. Pharmacol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2870","DOI":"10.1002\/elps.201400224","article-title":"Chiral analysis of amino acid neurotransmitters and neuromodulators in mouse brain by CE-LIF","volume":"35","author":"Jako","year":"2014","journal-title":"Electrophoresis"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"e2664","DOI":"10.21769\/BioProtoc.2664","article-title":"Preparation, Stimulation and Other Uses of Adult Rat Brain Synaptosomes","volume":"7","author":"Modi","year":"2017","journal-title":"Bio Protoc."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2816","DOI":"10.1002\/elps.201100032","article-title":"Comparison of quantitative performance of three fluorescence labels in CE\/LIF analysis of aspartate and glutamate in brain microdialysate","volume":"32","author":"Wagner","year":"2011","journal-title":"Electrophoresis"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/17\/9564\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:14:21Z","timestamp":1760141661000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/17\/9564"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,24]]},"references-count":46,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2022,9]]}},"alternative-id":["ijms23179564"],"URL":"https:\/\/doi.org\/10.3390\/ijms23179564","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8,24]]}}}