{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T00:53:24Z","timestamp":1760057604505,"version":"build-2065373602"},"reference-count":62,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2025,2,14]],"date-time":"2025-02-14T00:00:00Z","timestamp":1739491200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Brazilian funding agency Coordination for the Improvement of Higher Education Personnel (CAPES)","award":["UIDB\/04308\/2020","600 UIDP\/04308\/2020"],"award-info":[{"award-number":["UIDB\/04308\/2020","600 UIDP\/04308\/2020"]}]},{"name":"Federal University of Piau\u00ed (UFPI)","award":["UIDB\/04308\/2020","600 UIDP\/04308\/2020"],"award-info":[{"award-number":["UIDB\/04308\/2020","600 UIDP\/04308\/2020"]}]},{"name":"Portuguese Foundation for Science and Technology","award":["UIDB\/04308\/2020","600 UIDP\/04308\/2020"],"award-info":[{"award-number":["UIDB\/04308\/2020","600 UIDP\/04308\/2020"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background: Neuropathic pain can be triggered by chemotherapy drugs such as paclitaxel (PTX). Management of pain is limited by drugs\u2019 ineffectiveness and adverse effects. Isopulegol (ISO) is a monoterpene present in the essential oils of several aromatic plants and has promising pharmacological activities. Objectives: to evaluate the antinociceptive activity of ISO in a PTX-induced neuropathic pain model. Methods: the toxicity of ISO was evaluated in healthy and cancerous cells. Behavioral assessments were performed using the von Frey and acetone tests. We investigated the involvement of the GABAergic pathway, NMDA, TNF-\u03b1, and the release of GABA and glutamate in the presence of ISO. Results: ISO showed little or no cytotoxicity in U87 and MDA-MB-231 cells. In both acute and subacute treatment, ISO at doses of 25, 50, and 100 mg\/kg (* p &lt; 0.05) increased the mechanical nociceptive threshold of neuropathic animals compared to the control group and reduced thermal sensitivity. Its action was reversed by pre-treatment with flumazenil and potentiated by the NMDA antagonist, MK-801. TNF-\u03b1 and glutamate levels were reduced and GABA release was increased in the tests carried out. Conclusions: ISO shows low toxicity in neuronal cells and its association with PTX generated synergism in its cytotoxic action. The antinociceptive effect of ISO is due to activation of GABA and antagonism of NMDA receptors and involves the stabilization of neuronal plasma membranes leading to an imbalance in the release of neurotransmitters, favoring GABA-mediated inhibition over glutamatergic excitation.<\/jats:p>","DOI":"10.3390\/ph18020256","type":"journal-article","created":{"date-parts":[[2025,2,14]],"date-time":"2025-02-14T06:52:01Z","timestamp":1739515921000},"page":"256","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Anti-Hyperalgesic Effect of Isopulegol Involves GABA and NMDA Receptors in a Paclitaxel-Induced Neuropathic Pain Model"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6644-3571","authenticated-orcid":false,"given":"Deyna","family":"Martins","sequence":"first","affiliation":[{"name":"Post Graduate Program in Pharmacology, Laboratory of Pain Pharmacology, Medicinal Plants Research Center, Federal University of Piau\u00ed\u2014UFPI, Teresina 64049-550, Brazil"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7298-9423","authenticated-orcid":false,"given":"Boris","family":"Acha","sequence":"additional","affiliation":[{"name":"Post Graduate Program in Biotechnology\u2014RENORBIO, Federal University of Piau\u00ed\u2014UFPI, Teresina 64049-550, Brazil"}]},{"given":"Mickael","family":"Cavalcante","sequence":"additional","affiliation":[{"name":"Laboratory of Experimental Cancerology, Medicinal Plants Research Center, Federal University of Piau\u00ed\u2014UFPI, Teresina 64049-550, Brazil"}]},{"given":"Suellen","family":"Pereira","sequence":"additional","affiliation":[{"name":"Post Graduate Program in Pharmacology, Laboratory of Pain Pharmacology, Medicinal Plants Research Center, Federal University of Piau\u00ed\u2014UFPI, Teresina 64049-550, Brazil"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9843-2503","authenticated-orcid":false,"given":"Ana","family":"Viana","sequence":"additional","affiliation":[{"name":"Nursing Department, State University of Maranh\u00e3o (UEMA)-Campus Santa In\u00eas, Maranh\u00e3o 65306-219, Brazil"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6677-1543","authenticated-orcid":false,"given":"Flaviano Ribeiro","family":"Pinheiro-Neto","sequence":"additional","affiliation":[{"name":"Post Graduate Program in Pharmacology, Laboratory of Pain Pharmacology, Medicinal Plants Research Center, Federal University of Piau\u00ed\u2014UFPI, Teresina 64049-550, Brazil"}]},{"given":"Priscyla","family":"Mendes","sequence":"additional","affiliation":[{"name":"Post Graduate Program in Pharmacology, Laboratory of Pain Pharmacology, Medicinal Plants Research Center, Federal University of Piau\u00ed\u2014UFPI, Teresina 64049-550, Brazil"}]},{"given":"Dalton","family":"Dittz-J\u00fanior","sequence":"additional","affiliation":[{"name":"Laboratory of Experimental Cancerology, Medicinal Plants Research Center, Federal University of Piau\u00ed\u2014UFPI, Teresina 64049-550, Brazil"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3995-7614","authenticated-orcid":false,"given":"Francisco","family":"Oliveira","sequence":"additional","affiliation":[{"name":"Post Graduate Program in Pharmacology, Laboratory of Pain Pharmacology, Medicinal Plants Research Center, Federal University of Piau\u00ed\u2014UFPI, Teresina 64049-550, Brazil"}]},{"given":"Tatiana","family":"Ventura","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Farmacologia e Neurobiologia, Centro de Investiga\u00e7\u00e3o Farmacol\u00f3gica e Inova\u00e7\u00e3o Medicamentosa (MedInUP\/RISE-Health), Instituto de Ci\u00eancias Biom\u00e9dicas de Abel Salazar Universidade do Porto (ICBAS-UP), 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1387-8018","authenticated-orcid":false,"given":"Maria da Gra\u00e7a","family":"Lobo","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Farmacologia e Neurobiologia, Centro de Investiga\u00e7\u00e3o Farmacol\u00f3gica e Inova\u00e7\u00e3o Medicamentosa (MedInUP\/RISE-Health), Instituto de Ci\u00eancias Biom\u00e9dicas de Abel Salazar Universidade do Porto (ICBAS-UP), 4050-313 Porto, Portugal"}]},{"given":"F\u00e1tima","family":"Ferreirinha","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Farmacologia e Neurobiologia, Centro de Investiga\u00e7\u00e3o Farmacol\u00f3gica e Inova\u00e7\u00e3o Medicamentosa (MedInUP\/RISE-Health), Instituto de Ci\u00eancias Biom\u00e9dicas de Abel Salazar Universidade do Porto (ICBAS-UP), 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6114-9189","authenticated-orcid":false,"given":"Paulo","family":"Correia-de-S\u00e1","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Farmacologia e Neurobiologia, Centro de Investiga\u00e7\u00e3o Farmacol\u00f3gica e Inova\u00e7\u00e3o Medicamentosa (MedInUP\/RISE-Health), Instituto de Ci\u00eancias Biom\u00e9dicas de Abel Salazar Universidade do Porto (ICBAS-UP), 4050-313 Porto, Portugal"}]},{"given":"Fernanda","family":"Almeida","sequence":"additional","affiliation":[{"name":"Post Graduate Program in Pharmacology, Laboratory of Pain Pharmacology, Medicinal Plants Research Center, Federal University of Piau\u00ed\u2014UFPI, Teresina 64049-550, Brazil"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1976","DOI":"10.1097\/j.pain.0000000000001939","article-title":"The revised International Association for the Study of Pain 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