{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T16:46:26Z","timestamp":1781196386862,"version":"3.54.1"},"reference-count":45,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2021,5,14]],"date-time":"2021-05-14T00:00:00Z","timestamp":1620950400000},"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>Nonsteroidal anti-inflammatory drugs (NSAIDs) are very commonly used, but their adverse effects warrant investigating new therapeutic alternatives. Polyalthic acid, a labdane-type diterpenoid, is known to produce gastroprotection, tracheal smooth muscle relaxation, and antitumoral, antiparasitic and antibacterial activity. This study aimed to evaluate the antinociceptive, antiallodynic, antihyperalgesic and anti-inflammatory effect of polyalthic acid on rats. Moreover, the effectiveness of treating hyperalgesia with a combination of polyalthic acid and naproxen was analyzed, as well as the type of drug\u2013drug interaction involved. Nociception was examined by injecting 1% formalin into the right hind paw and thermal hyperalgesia and inflammation by injecting a 1% carrageenan solution into the left hind paw of rats. Allodynia was assessed on an L5\/L6 spinal nerve ligation model. Polyalthic acid generated significant antinociceptive (56\u2013320 mg\/kg), antiallodynic (100\u2013562 mg\/kg), and antihyperalgesic and anti-inflammatory (10\u2013178 mg\/kg) effects. Antinociception mechanisms were explored by pretreating the rats with naltrexone, ODQ and methiothepin, finding the effect blocked by the former two compounds, which indicates the participation of opioid receptors and guanylate cyclase. An isobolographic analysis suggests synergism between polyalthic acid and naproxen in the combined treatment of hyperalgesia.<\/jats:p>","DOI":"10.3390\/molecules26102921","type":"journal-article","created":{"date-parts":[[2021,5,14]],"date-time":"2021-05-14T10:54:22Z","timestamp":1620989662000},"page":"2921","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Evaluation of the Antinociceptive, Antiallodynic, Antihyperalgesic and Anti-Inflammatory Effect of Polyalthic Acid"],"prefix":"10.3390","volume":"26","author":[{"given":"Juan","family":"Rodr\u00edguez-Silverio","sequence":"first","affiliation":[{"name":"Escuela Superior de Medicina, Instituto Polit\u00e9cnico Nacional, Plan de San Luis y D\u00edaz Mir\u00f3n, Colonia Casco de Santo Tom\u00e1s, Miguel Hidalgo, Ciudad de M\u00e9xico 11340, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda Elena","family":"S\u00e1nchez-Mendoza","sequence":"additional","affiliation":[{"name":"Escuela Superior de Medicina, Instituto Polit\u00e9cnico Nacional, Plan de San Luis y D\u00edaz Mir\u00f3n, Colonia Casco de Santo Tom\u00e1s, Miguel Hidalgo, Ciudad de M\u00e9xico 11340, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H\u00e9ctor Isaac","family":"Rocha-Gonz\u00e1lez","sequence":"additional","affiliation":[{"name":"Escuela Superior de Medicina, Instituto Polit\u00e9cnico Nacional, Plan de San Luis y D\u00edaz Mir\u00f3n, Colonia Casco de Santo Tom\u00e1s, Miguel Hidalgo, Ciudad de M\u00e9xico 11340, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan Gerardo","family":"Reyes-Garc\u00eda","sequence":"additional","affiliation":[{"name":"Escuela Superior de Medicina, Instituto Polit\u00e9cnico Nacional, Plan de San Luis y D\u00edaz Mir\u00f3n, Colonia Casco de Santo Tom\u00e1s, Miguel Hidalgo, Ciudad de M\u00e9xico 11340, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco Javier","family":"Flores-Murrieta","sequence":"additional","affiliation":[{"name":"Escuela Superior de Medicina, Instituto Polit\u00e9cnico Nacional, Plan de San Luis y D\u00edaz Mir\u00f3n, Colonia Casco de Santo Tom\u00e1s, Miguel Hidalgo, Ciudad de M\u00e9xico 11340, Mexico"},{"name":"Unidad de Investigaci\u00f3n en Farmacolog\u00eda, Instituto Nacional de Enfermedades Respiratorias Ismael Cosi\u00f3 Villegas, Secretar\u00eda de Salud, Ciudad de M\u00e9xico 14080, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaraset","family":"L\u00f3pez-Lorenzo","sequence":"additional","affiliation":[{"name":"Escuela Superior de Medicina, Instituto Polit\u00e9cnico Nacional, Plan de San Luis y D\u00edaz Mir\u00f3n, Colonia Casco de Santo Tom\u00e1s, Miguel Hidalgo, Ciudad de M\u00e9xico 11340, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geovanna Nallely","family":"Qui\u00f1onez-Bastidas","sequence":"additional","affiliation":[{"name":"Escuela Superior de Medicina, Instituto Polit\u00e9cnico Nacional, Plan de San Luis y D\u00edaz Mir\u00f3n, Colonia Casco de Santo Tom\u00e1s, Miguel Hidalgo, Ciudad de M\u00e9xico 11340, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2928-744X","authenticated-orcid":false,"given":"Jes\u00fas","family":"Arrieta","sequence":"additional","affiliation":[{"name":"Escuela Superior de Medicina, Instituto Polit\u00e9cnico Nacional, Plan de San Luis y D\u00edaz Mir\u00f3n, Colonia Casco de Santo Tom\u00e1s, Miguel Hidalgo, Ciudad de M\u00e9xico 11340, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,5,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0301-0082(98)00048-3","article-title":"The induction of pain: An integrative review","volume":"57","author":"Millan","year":"1999","journal-title":"Prog. Neurobiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2420","DOI":"10.1097\/j.pain.0000000000000613","article-title":"Updating the definition of pain","volume":"157","author":"Williams","year":"2016","journal-title":"Pain"},{"key":"ref_3","first-page":"537","article-title":"A group randomized trial to improve safe use of nonsteroidal anti-inflammatory drugs","volume":"11","author":"Curtis","year":"2005","journal-title":"Am. J. Manag. Care"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/ar4173","article-title":"Nonsteroidal anti-inflammatory drugs and their risk: A story still in development","volume":"15","author":"Simon","year":"2013","journal-title":"Arthritis Res. Ther."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1016\/j.tips.2009.01.001","article-title":"Cyclooxygenase-inhibiting nitric oxide donators for osteoarthritis","volume":"30","author":"Wallace","year":"2009","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"957","DOI":"10.1111\/bcp.13048","article-title":"Cardiovascular effects of cyclooxygenase-2 inhibitors: A mechanistic and clinical perspective","volume":"82","author":"Carlo","year":"2016","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"95","DOI":"10.2147\/vhrm.2006.2.2.95","article-title":"Risk of Cardiovascular Events and Cyclooxygenase-2 Inhibitors","volume":"2","author":"Reza","year":"2006","journal-title":"Vasc. Health. Risk. Manag."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/j.bmcl.2009.11.024","article-title":"Gastroprotective flavonoid constituents from Oroxylum indicum Vent","volume":"20","author":"Babu","year":"2010","journal-title":"Bioorganic Med. Chem. Lett."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"4418","DOI":"10.1021\/cr100258k","article-title":"Isolation, Chemical, and Biotransformation Routes of Labdane-type Diterpenes","volume":"111","author":"Frija","year":"2011","journal-title":"Chem. Rev."},{"key":"ref_10","first-page":"931","article-title":"Bioassay-guided isolation of an anti-ulcer diterpenoid from Croton reflexifolius: Role of nitric oxide, prostaglandins and sulfhydryls","volume":"60","author":"Arrieta","year":"2008","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"800","DOI":"10.1080\/13880200802315881","article-title":"Polyalthic Acid Isolated from Croton reflexifolius has Relaxing Effect in Guinea Pig Tracheal Smooth Muscle","volume":"46","author":"Arrieta","year":"2008","journal-title":"Pharm. Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1016\/j.fitote.2013.02.009","article-title":"Lipophilic components from Fructus Viticis Negundo and their anti-tumor activities","volume":"86","author":"Huang","year":"2013","journal-title":"Fitoterapia"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1348","DOI":"10.1002\/cbdv.201600065","article-title":"Copaifera duckei Oleoresin and Its Main Nonvolatile Terpenes: In Vitro Schistosomicidal Properties","volume":"13","author":"Borges","year":"2016","journal-title":"Chem. Biodivers."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.anaerobe.2016.04.017","article-title":"Copaifera reticulata oleoresin: Chemical characterization and antibacterial properties against oral pathogens","volume":"40","author":"Bianchi","year":"2016","journal-title":"Anaerobe"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1159\/000097233","article-title":"Inflammatory responses to carrageenan injection in LEW\/N and F344\/N rats: LEW\/N rats show sex- and age-dependent changes in inflammatory reactions","volume":"3","author":"Misiewicz","year":"1996","journal-title":"Neuroimmunomodulation"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1016\/j.neulet.2003.09.081","article-title":"Effects of gender and gonadal hormones on nociceptive responses to intraplantar carrageenan in the rat","volume":"354","author":"Tall","year":"2004","journal-title":"Neurosci. Lett."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2386","DOI":"10.1152\/jappl.2001.90.6.2386","article-title":"An automated flinch detecting system for use in the formalin nociceptive bioassay","volume":"90","author":"Yaksh","year":"2001","journal-title":"J. Appl. Physiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/S0091-3057(01)00506-8","article-title":"Estrous cycle modulation of nociceptive behaviors elicited by electrical stimulation and formalin","volume":"69","author":"Vincler","year":"2001","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1016\/0031-9384(95)00099-5","article-title":"Behavioural effects of different intensities of formalin pain in rats","volume":"58","author":"Aloisi","year":"1995","journal-title":"Physiol. Behav."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1016\/0006-8993(95)00912-A","article-title":"Sex-related effects on behaviour and beta-endorphin of different intensities of formalin pain in rats","volume":"699","author":"Aloisi","year":"1995","journal-title":"Brain Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.ejphar.2007.06.034","article-title":"Subcutaneous, intrathecal and periaqueductal grey administration of asimadoline and ICI-204448 reduces tactile allodynia in the rat","volume":"573","author":"Bartoszyk","year":"2007","journal-title":"Eur. J. Pharmacol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1016\/j.pain.2010.08.014","article-title":"Direct blockade of inflammatory hypernociception by peripheral A1 adenosine receptors: Involvement of the NO\/cGMP\/PKG\/KATP signaling pathway","volume":"151","author":"Lima","year":"2010","journal-title":"Pain"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1038\/sj.bjp.0704224","article-title":"Dibutyryl-cyclic GMP induces peripheral antinociception via activation of ATP-sensitive K+ channels in the rat PGE2 -induced hyperalgesic paw","volume":"134","author":"Soares","year":"2001","journal-title":"Br. J. Pharmacol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1038\/sj.bjp.0702601","article-title":"Pharmacological modulation of secondary mediator systems-cyclic AMP and cyclic GMP-on inflammatory hyperalgesia","volume":"127","author":"Cunha","year":"1999","journal-title":"Br. J. Pharmacol."},{"key":"ref_25","first-page":"CD006605","article-title":"Long-term opioid management for chronic noncancer pain","volume":"2010","author":"Noble","year":"2010","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/j.pbb.2004.12.002","article-title":"A preclinical comparison between different opioids: Antinociceptive versus adverse effects","volume":"80","author":"Meert","year":"2005","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.brainres.2009.11.020","article-title":"Role of nitric oxide in the rat hippocampal CA1 in morphine antinociception","volume":"1313","author":"Hashemi","year":"2010","journal-title":"Brain Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/0014-2999(91)90333-L","article-title":"The molecular mechanism of action of peripheral morphine analgesia: Stimulation of the cGMP system via nitric oxide release","volume":"201","author":"Ferreira","year":"1991","journal-title":"Eur. J. Pharmacol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.niox.2015.02.146","article-title":"Involvement of the NO\/cGMP\/KATP pathway in the antinociceptive effect of the new pyrazole 5-(1-(3-fluorophenyl)-1H-pyrazol-4-yl)-2H-tetrazole (LQFM-021)","volume":"47","author":"Florentino","year":"2015","journal-title":"Nitric Oxide."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"4442","DOI":"10.1073\/pnas.0914733107","article-title":"Morphine peripheral analgesia depends on activation of the PI3Kgamma\/AKT\/nNOS\/NO\/KATP signaling pathway","volume":"107","author":"Cunha","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1186\/1744-8069-8-10","article-title":"Stimulation of Peripheral Kappa Opioid Receptors Inhibits Inflammatory Hyperalgesia via Activation of the PI3K\u03b3\/AKT\/nNOS\/NO Signaling Pathway","volume":"8","author":"Cunha","year":"2012","journal-title":"Mol. Pain"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"34950","DOI":"10.1074\/jbc.M110.162982","article-title":"Molecular basis for cyclooxygenase inhibition by the non-steroidal anti-inflammatory drug naproxen","volume":"285","author":"Duggan","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2014\/436123","article-title":"Nonsteroidal Anti-Inflammatory Drugs and Prostatic Diseases","volume":"2014","author":"Ishiguro","year":"2014","journal-title":"BioMed. Res. Int."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1143","DOI":"10.1016\/j.jtcvs.2010.06.057","article-title":"Effects of selective cyclooxygenase-2 and nonselective cyclooxygenase inhibition on ischemic myocardium","volume":"140","author":"Robich","year":"2010","journal-title":"J. Thorac. Cardiovasc. Surg."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.phymed.2010.05.009","article-title":"Synergistic effect of the interaction between naproxen and citral on inflammation in rats","volume":"18","author":"Ortiz","year":"2010","journal-title":"Phytomedicine"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"113742","DOI":"10.1016\/j.jep.2020.113742","article-title":"The anti-inflammatory and analgesic activities of the ethyl acetate extract of Viburnum taitoense Hayata","volume":"6","author":"Wu","year":"2021","journal-title":"J. Ethnopharmacol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"R473","DOI":"10.1152\/ajpregu.00355.2012","article-title":"Reciprocal regulation of the nitric oxide and cyclooxygenase pathway in pathophysiology: Relevance and clinical implications","volume":"304","author":"Salvemini","year":"2013","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/0304-3959(83)90201-4","article-title":"Ethical guidelines for investigations of experimental pain in conscious animals","volume":"16","author":"Zimmermann","year":"1983","journal-title":"Pain"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1007\/BF02244551","article-title":"Standardization of the rat paw formalin test for the evaluation of analgesics","volume":"104","author":"Cowan","year":"1991","journal-title":"Psychopharmacology"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1016\/0304-3959(92)90041-9","article-title":"An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat","volume":"50","author":"Kim","year":"1992","journal-title":"Pain"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/0165-0270(94)90144-9","article-title":"Quantitative assessment of tactile allodynia in the rat paw","volume":"53","author":"Chaplan","year":"1994","journal-title":"J. Neurosci. Methods"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/0304-3959(88)90026-7","article-title":"A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia","volume":"32","author":"Hargreaves","year":"1988","journal-title":"Pain"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1159\/000101390","article-title":"Isobolographic Analyses of the Gabapentin-Metamizol Combination after Local Peripheral, Intrathecal and Oral Administration in the Rat","volume":"79","author":"Herrera","year":"2007","journal-title":"Pharmacology"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Tallarida, R. (2000). Calculations for Combination Drug Analysis. Drug Synergism and Dose-Effect Data Analysis, Chapman and Hall\/CRC.","DOI":"10.1201\/9781420036107"},{"key":"ref_45","first-page":"174","article-title":"Rapid foot volume measurements on unanesthetized rats, and the question of a phe-nylbutazone effect on anaphylactoid edema","volume":"112","author":"Winder","year":"1957","journal-title":"Arch. Int. Pharmacodyn. Ther."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/26\/10\/2921\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:00:51Z","timestamp":1760162451000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/26\/10\/2921"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,14]]},"references-count":45,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2021,5]]}},"alternative-id":["molecules26102921"],"URL":"https:\/\/doi.org\/10.3390\/molecules26102921","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,14]]}}}