{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T05:40:50Z","timestamp":1782452450949,"version":"3.54.5"},"reference-count":49,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T00:00:00Z","timestamp":1773792000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Fibromyalgia (FM) is a chronic painful condition that primarily affects women. The allodynia and hyperalgesia induced by reserpine is a FM model commonly used to study the disease; however, it produces one painful episode, in contrast to FM, which is a chronic painful condition. Reserpine induces hypersensitivity for 10 days, which is resolved by day-21. In this study, we sought to determine whether the resolution of pain was due to the release of endogenous antinociceptive opioids and the activation of spinal opioid receptors.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Female Wistar rats were used in this study. To induce a fibromyalgia-like model, reserpine was subcutaneously administered. Twenty-one days after reserpine administration, subcutaneous or intrathecal opioid blockers were administered to evaluate latent sensitization. Additionally, serum \u03b2-endorphin concentration was determined by ELISA.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Reserpine produced transitory hyperalgesia and allodynia, which was resolved by day 21. Systemic administration of naloxone on days 21, 33, and 45 reinstated hypersensitivity. Likewise, intrathecal administration of naltrexone or specific antagonists of\n                      <jats:bold>\u03bc<\/jats:bold>\n                      and\n                      <jats:bold>\u03b4<\/jats:bold>\n                      opioid receptors (CTOP and naltrindole) reinstated hypersensitivity. These results suggest that an increased concentration of opioid agonists in reserpinized animals leads to antinociceptive effects. Accordingly, reserpine injection enhanced serum \u03b2-endorphin concentration in female rats.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our data suggest that reserpine-induced nociceptive hypersensitivity is a long-lasting condition masked by the compensatory release of \u03b2-endorphin and the activation of spinal \u00b5 and, to a lesser extent, \u03b4 opioid receptors.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1733691","type":"journal-article","created":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T06:58:04Z","timestamp":1773817084000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Reserpine-induced fibromyalgia model in female rats is a long-lasting painful condition masked by antinociceptive endogenous opioids"],"prefix":"10.3389","volume":"17","author":[{"given":"Cristina","family":"Ju\u00e1rez-N\u00fa\u00f1ez","sequence":"first","affiliation":[{"name":"Laboratorio de Fisiolog\u00eda Celular, Instituto Nacional de Psiquiatr\u00eda Ram\u00f3n de la Fuente Mu\u00f1iz","place":["Ciudad de M\u00e9xico, Mexico"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pedro","family":"Segura-Chama","sequence":"additional","affiliation":[{"name":"Laboratorio de Fisiolog\u00eda Celular, Instituto Nacional de Psiquiatr\u00eda Ram\u00f3n de la Fuente Mu\u00f1iz","place":["Ciudad de M\u00e9xico, Mexico"]},{"name":"Investigador por M\u00e9xico, Secretar\u00eda de Ciencias, Humanidades, Tecnolog\u00eda e Innovaci\u00f3n","place":["Ciudad de M\u00e9xico, Mexico"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan Miguel","family":"Piza\u00f1a-Encarnaci\u00f3n","sequence":"additional","affiliation":[{"name":"Neurobiology of Pain Laboratory, Departamento de Farmacobiolog\u00eda, Cinvestav, South Campus","place":["Mexico City, Mexico"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco","family":"Pellicer","sequence":"additional","affiliation":[{"name":"Laboratorio de Neurofisiolog\u00eda Integrativa, Instituto Nacional de Psiquiatr\u00eda Ram\u00f3n de la Fuente Mu\u00f1iz","place":["Ciudad de M\u00e9xico, Mexico"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vinicio","family":"Granados-Soto","sequence":"additional","affiliation":[{"name":"Neurobiology of Pain Laboratory, Departamento de Farmacobiolog\u00eda, Cinvestav, South Campus","place":["Mexico City, Mexico"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco","family":"Mercado","sequence":"additional","affiliation":[{"name":"Laboratorio de Fisiolog\u00eda Celular, Instituto Nacional de Psiquiatr\u00eda Ram\u00f3n de la Fuente Mu\u00f1iz","place":["Ciudad de M\u00e9xico, Mexico"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ang\u00e9lica","family":"Almanza","sequence":"additional","affiliation":[{"name":"Laboratorio de Fisiolog\u00eda Celular, Instituto Nacional de Psiquiatr\u00eda Ram\u00f3n de la Fuente Mu\u00f1iz","place":["Ciudad de M\u00e9xico, Mexico"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,3,18]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1016\/j.pbb.2015.08.013","article-title":"A D2-like receptor family agonist produces analgesia in mechanonociception but not in thermonociception at the spinal cord level in rats","volume":"137","author":"Almanza","year":"2015","journal-title":"Pharmacol. Biochem. Behav."},{"key":"B2","doi-asserted-by":"publisher","first-page":"9719","DOI":"10.1038\/s41598-022-13968-7","article-title":"Long-lasting reflexive and nonreflexive pain responses in two mouse models of fibromyalgia-like condition","volume":"12","author":"\u00c1lvarez-P\u00e9rez","year":"2022","journal-title":"Sci. Rep."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1155\/2022\/1217717","article-title":"Analgesic medication in fibromyalgia patients: a cross-sectional study","volume":"2022","author":"Aster","year":"2022","journal-title":"Pain Res. Manag."},{"key":"B4","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1016\/j.pain.2006.02.017","article-title":"Loss of spinal mu-opioid receptor is associated with mechanical allodynia in a rat model of peripheral neuropathy","volume":"123","author":"Back","year":"2006","journal-title":"Pain"},{"key":"B5","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1186\/1471-2474-5-48","article-title":"Cerebrospinal fluid levels of opioid peptides in fibromyalgia and chronic low back pain","volume":"5","author":"Baraniuk","year":"2004","journal-title":"BMC Musculoskelet. Disord."},{"key":"B6","doi-asserted-by":"publisher","first-page":"e1080","DOI":"10.1097\/PR9.0000000000001080","article-title":"Low-dose naltrexone for treatment of pain in patients with fibromyalgia: a randomized, double-blind, placebo-controlled, crossover study","volume":"8","author":"Bested","year":"2023","journal-title":"Pain Rep."},{"key":"B7","doi-asserted-by":"publisher","first-page":"107959","DOI":"10.1016\/j.pharmthera.2021.107959","article-title":"Animal models of fibromyalgia: what is the best choice?","volume":"230","author":"Brum","year":"2022","journal-title":"Pharmacol. Ther."},{"key":"B8","doi-asserted-by":"publisher","first-page":"140","DOI":"10.3344\/kjp.25275","article-title":"Low-dose naltrexone for fibromyalgia: a re-analysis suggests lower efficacy than previously reported","volume":"39","author":"Bruun","year":"2026","journal-title":"Korean J. Pain"},{"key":"B9","doi-asserted-by":"publisher","first-page":"498149","DOI":"10.1073\/pnas.2211631120","article-title":"Neutrophils infiltrate sensory ganglia and mediate chronic widespread pain in fibromyalgia","volume":"120","author":"Caxaria","year":"2023","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B10","doi-asserted-by":"publisher","first-page":"108253","DOI":"10.1016\/j.neuropharm.2020.108253","article-title":"Neurokinin 1 receptor activation in the rat spinal cord maintains latent sensitization, a model of inflammatory and neuropathic chronic pain","volume":"177","author":"Chen","year":"2020","journal-title":"Neuropharmacology"},{"key":"B11","doi-asserted-by":"publisher","first-page":"1394","DOI":"10.1126\/science.1239403","article-title":"Constitutive \u03bc-opioid receptor activity leads to long-term endogenous analgesia and dependence","volume":"341","author":"Corder","year":"2013","journal-title":"Science"},{"key":"B12","doi-asserted-by":"publisher","first-page":"107726","DOI":"10.1016\/j.neuropharm.2019.107726","article-title":"Sex differences in kappa opioid receptor inhibition of latent postoperative pain sensitization in dorsal horn","volume":"163","author":"Custodio-Patsey","year":"2020","journal-title":"Neuropharmacology"},{"key":"B13","doi-asserted-by":"publisher","first-page":"1268","DOI":"10.1016\/j.jpain.2022.02.008","article-title":"The influence of opioids on transcutaneous electrical nerve stimulation effects in women with fibromyalgia","volume":"23","author":"Dailey","year":"2022","journal-title":"J. Pain"},{"key":"B14","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1016\/S0361-9230(02)00866-3","article-title":"A procedure for direct lumbar puncture in rats","volume":"59","author":"De La Calle","year":"2002","journal-title":"Brain Res. Bull."},{"key":"B15","doi-asserted-by":"publisher","first-page":"172443","DOI":"10.1016\/j.ejphar.2019.172443","article-title":"Blockade of spinal \u03b15-GABAA receptors differentially reduces reserpine-induced fibromyalgia-type pain in female rats","volume":"858","author":"De la Luz-Cuellar","year":"2019","journal-title":"Eur. J. Pharmacol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"175696","DOI":"10.1016\/j.ejphar.2023.175696","article-title":"Spinal dopaminergic D1-and D2-like receptors have a sex-dependent effect in an experimental model of fibromyalgia","volume":"948","author":"De la Luz-Cuellar","year":"2023","journal-title":"Eur. J. Pharmacol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"e31","DOI":"10.1016\/S2665-9913(23)00278-3","article-title":"Naltrexone 6 mg once daily versus placebo in women with fibromyalgia: a randomised, double-blind, placebo-controlled trial","volume":"6","author":"Due Bruun","year":"2024","journal-title":"Lancet Rheumatol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"175","DOI":"10.3758\/BF03193146","article-title":"G*Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences","volume":"39","author":"Faul","year":"2007","journal-title":"Behav. Res. Methods"},{"key":"B19","doi-asserted-by":"publisher","first-page":"102024","DOI":"10.1016\/j.npep.2020.102024","article-title":"Neuropeptide Y tonically inhibits an NMDAR\u2794AC1\u2794TRPA1\/TRPV1 mechanism of the affective dimension of chronic neuropathic pain","volume":"80","author":"Fu","year":"2020","journal-title":"Neuropeptides"},{"key":"B20","doi-asserted-by":"publisher","first-page":"e144201","DOI":"10.1172\/JCI144201","article-title":"Passive transfer of fibromyalgia symptoms from patients to mice","volume":"131","author":"Goebel","year":"2021","journal-title":"J. Clin. Investigation"},{"key":"B49","doi-asserted-by":"publisher","first-page":"11820","DOI":"10.1073\/pnas.2000712117","article-title":"Biased signaling by endogenous opioid peptides","volume":"117","author":"Gomes","year":"2020","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"key":"B21","doi-asserted-by":"publisher","first-page":"10000","DOI":"10.1523\/JNEUROSCI.2849-07.2007","article-title":"Decreased central mu-opioid receptor availability in fibromyalgia","volume":"27","author":"Harris","year":"2007","journal-title":"J. Neurosci."},{"key":"B22","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1016\/j.yhbeh.2017.10.011","article-title":"Sex differences and estradiol involvement in hyperalgesia and allodynia in an experimental model of fibromyalgia","volume":"97","author":"Hernandez-Leon","year":"2018","journal-title":"Horm. Behav."},{"key":"B23","doi-asserted-by":"publisher","first-page":"147298","DOI":"10.1016\/j.brainres.2021.147298","article-title":"The \u00b5-\u03b4 opioid heteromer masks latent pain sensitization in neuropathic and inflammatory pain in male and female mice","volume":"1756","author":"Inyang","year":"2021","journal-title":"Brain Res."},{"key":"B24","first-page":"209","article-title":"Fibromyalgia, autism, and opioid addiction as natural and induced disorders of the endogenous opioid hormonal system","volume":"18","author":"Johnson","year":"2014","journal-title":"Discov. Med."},{"key":"B25","doi-asserted-by":"publisher","first-page":"118","DOI":"10.1016\/j.neulet.2013.03.026","article-title":"Role of spinal opioid receptor on the antiallodynic effect of intrathecal nociceptin in neuropathic rat","volume":"542","author":"Ju","year":"2013","journal-title":"Neurosci. Lett."},{"key":"B26","doi-asserted-by":"publisher","first-page":"347","DOI":"10.2217\/pmt-2016-0012","article-title":"Is there a role for opioids in the treatment of fibromyalgia?","volume":"6","author":"Littlejohn","year":"2016","journal-title":"Pain Manag."},{"key":"B27","doi-asserted-by":"publisher","first-page":"783","DOI":"10.1007\/s10067-020-05528-z","article-title":"Dorsal root ganglia: fibromyalgia pain factory?","volume":"40","author":"Mart\u00ednez-Lav\u00edn","year":"2021","journal-title":"Clin. Rheumatol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1002\/0471142301.ns0950s71","article-title":"Latent sensitization: a model for stress-sensitive chronic pain","volume":"71","author":"Marvizon","year":"2015","journal-title":"Curr. Protoc. Neurosci."},{"key":"B29","doi-asserted-by":"publisher","first-page":"2812","DOI":"10.3390\/IJMS24032812","article-title":"Evidence for endogenous opioid dependence related to latent sensitization in a rat model of chronic inflammatory pain","volume":"24","author":"Morales-Medina","year":"2023","journal-title":"Int. J. Mol. Sci."},{"key":"B30","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1016\/j.pain.2009.05.024","article-title":"Biogenic amine depletion causes chronic muscular pain and tactile allodynia accompanied by depression: a putative animal model of fibromyalgia","volume":"146","author":"Nagakura","year":"2009","journal-title":"Pain"},{"key":"B31","doi-asserted-by":"publisher","first-page":"1035","DOI":"10.55563\/CLINEXPRHEUMATOL\/RFY9HB","article-title":"Correlation between nocturnal heart rate variability parameters and circulating neuropeptides in patients suffering from fibromyalgia","volume":"43","author":"Navarro-Gonzalez","year":"2025","journal-title":"Clin. Exp. Rheumatol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"363","DOI":"10.1080\/15360288.2025.2496526","article-title":"Efficacy of low-dose naltrexone in treating patients with fibromyalgia: systematic review and meta-analysis","volume":"39","author":"Ologunowa","year":"2025","journal-title":"J. Pain Palliat. Care Pharmacother."},{"key":"B33","doi-asserted-by":"publisher","first-page":"270","DOI":"10.1097\/00002508-200207000-00008","article-title":"Peripheral blood mononuclear cell beta-endorphin concentration is decreased in chronic fatigue syndrome and fibromyalgia but not in depression: preliminary report","volume":"18","author":"Panerai","year":"2002","journal-title":"Clin. J. Pain"},{"key":"B34","doi-asserted-by":"publisher","first-page":"105746","DOI":"10.1016\/j.yhbeh.2025.105746","article-title":"Activational and organizational actions of gonadal hormones on the sexual dimorphism of the \u03b16-subunit containing GABAA receptor in Wistar rats with neuropathic pain","volume":"171","author":"Piza\u00f1a-Encarnaci\u00f3n","year":"2025","journal-title":"Horm. Behav."},{"key":"B35","doi-asserted-by":"publisher","first-page":"356","DOI":"10.1007\/s11916-013-0356-5","article-title":"Worldwide epidemiology of fibromyalgia","volume":"17","author":"Queiroz","year":"2013","journal-title":"Curr. Pain Headache Rep."},{"key":"B36","doi-asserted-by":"publisher","first-page":"550","DOI":"10.1002\/art.1780350509","article-title":"Cerebrospinal fluid biogenic amine metabolites in fibromyalgia\/fibrositis syndrome and rheumatoid arthritis","volume":"35","author":"Russell","year":"1992","journal-title":"Arthritis Rheum."},{"key":"B37","doi-asserted-by":"publisher","first-page":"645","DOI":"10.1038\/s41584-020-00506-w","article-title":"Fibromyalgia: an update on clinical characteristics, aetiopathogenesis and treatment","volume":"16","author":"Sarzi-Puttini","year":"2020","journal-title":"Nat. Rev. Rheumatol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"1607","DOI":"10.1097\/j.pain.0000000000001247","article-title":"Mu-opioid receptors in nociceptive afferents produce a sustained suppression of hyperalgesia in chronic pain","volume":"159","author":"Severino","year":"2018","journal-title":"Pain"},{"key":"B39","doi-asserted-by":"publisher","first-page":"513","DOI":"10.1124\/jpet.109.152678","article-title":"The relative potency of inverse opioid agonists and a neutral opioid antagonist in precipitated withdrawal and antagonism of Analgesia and toxicity","volume":"330","author":"Sirohi","year":"2009","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"B40","doi-asserted-by":"publisher","first-page":"114","DOI":"10.1016\/j.neuroscience.2016.06.006","article-title":"Neurobiology of fibromyalgia and chronic widespread pain","volume":"338","author":"Sluka","year":"2016","journal-title":"Neuroscience"},{"key":"B41","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1002\/1097-4598(200101)24:1<37::AID-MUS4>3.0.CO;2-8","article-title":"Unilateral intramuscular injections of acidic saline produce a bilateral, long-lasting hyperalgesia","volume":"24","author":"Sluka","year":"2001","journal-title":"Muscle Nerve"},{"key":"B42","doi-asserted-by":"publisher","first-page":"415","DOI":"10.1097\/01.j.pain.0000460334.49525.5e","article-title":"Peripheral and spinal mechanisms of nociception in a rat reserpine-induced pain model","volume":"156","author":"Taguchi","year":"2015","journal-title":"Pain"},{"key":"B43","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1016\/0304-3959(91)90068-9","article-title":"No evidence for endorphin deficiency in fibromyalgia following investigation of cerebrospinal fluid (CSF) dynorphin A and Met-enkephalin-Arg6-Phe7","volume":"46","author":"Vaer\u00f8y","year":"1991","journal-title":"Pain"},{"key":"B44","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1523\/JNEUROSCI.1751-15.2016","article-title":"Sustained suppression of hyperalgesia during latent sensitization by \u03bc-\u03b4-and \u03ba-opioid receptors and \u03b12A adrenergic receptors: role of constitutive activity","volume":"36","author":"Walwyn","year":"2016","journal-title":"J. Neurosci."},{"key":"B45","doi-asserted-by":"publisher","first-page":"600","DOI":"10.1002\/acr.20140","article-title":"The American college of rheumatology preliminary diagnostic criteria for fibromyalgia and measurement of symptom severity","volume":"62","author":"Wolfe","year":"2010","journal-title":"Arthritis Care Res. Hob."},{"key":"B46","doi-asserted-by":"publisher","first-page":"319","DOI":"10.1016\/j.semarthrit.2016.08.012","article-title":"2016 Revisions to the 2010\/2011 fibromyalgia diagnostic criteria","volume":"46","author":"Wolfe","year":"2016","journal-title":"Semin. Arthritis Rheum."},{"key":"B47","first-page":"183","article-title":"Serum beta-endorphin in primary fibromyalgia syndrome: a controlled study","volume":"13","author":"Yunus","year":"1986","journal-title":"J. Rheumatol."},{"key":"B48","doi-asserted-by":"publisher","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"}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1733691\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T06:58:06Z","timestamp":1773817086000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1733691\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,18]]},"references-count":49,"alternative-id":["10.3389\/fphar.2026.1733691"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2026.1733691","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,18]]},"article-number":"1733691"}}