{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T22:35:50Z","timestamp":1790202950808,"version":"4.1.0"},"reference-count":42,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2025,12,18]],"date-time":"2025-12-18T00:00:00Z","timestamp":1766016000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministerio de Ciencia, Innovaci\u00f3n y Universidades, Instituto de Salud Carlos III, Fondo Europeo de Desarrollo Regional (FEDER), Uni\u00f3n Europea","award":["PI21\/00592"],"award-info":[{"award-number":["PI21\/00592"]}]},{"name":"CERCA Programe\/Generalitat de Catalunya"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Neuropathic pain (NP) is a complex and disabling condition that often requires long-term treatment with high doses of pharmacological agents, frequently resulting in significant adverse side effects. Therefore, safer and more effective therapeutic approaches are urgently needed. Molecular hydrogen, recognized for its antioxidant and anti-inflammatory actions, may act as a valuable adjunct to conventional analgesics. This study examined whether hydrogen-rich water (HRW) could potentiate the analgesic effects of JWH-133, a selective cannabinoid receptor type 2 agonist, and pregabalin, a gabapentinoid, in male C57BL\/6 mice with NP induced by chronic constriction of the sciatic nerve. Mechanical allodynia, thermal hyperalgesia, and cold allodynia were assessed following separate or combined administration of HRW with JWH-133 or pregabalin. Western blot analyses of dorsal root ganglia measured markers of oxidative stress (4-HNE), inflammation (NLRP3), synaptic plasticity (p-ERK), and nociceptive signaling (p-AKT). Each treatment reduced pain-like behaviors in a dose-dependent manner, while co-administration of HRW with JWH-133 or pregabalin produced greater analgesic effects. Combined treatments also diminished oxidative stress, inflammation, maladaptive neural changes and nociceptive pathways activated by peripheral nerve injury. These findings suggest HRW as a promising adjuvant to cannabinoid and gabapentinoid therapies, potentially improving efficacy and reducing high-dose drug-related adverse effects.<\/jats:p>","DOI":"10.3390\/ijms262412155","type":"journal-article","created":{"date-parts":[[2025,12,18]],"date-time":"2025-12-18T09:15:21Z","timestamp":1766049321000},"page":"12155","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Hydrogen-Rich Water Potentiates Cannabinoid- and Gabapentinoid-Induced Analgesia in Neuropathic Pain"],"prefix":"10.3390","volume":"26","author":[{"given":"Nuria Andrea","family":"Tort","sequence":"first","affiliation":[{"name":"Grup de Neurofarmacologia Molecular, Institut de Recerca Sant Pau (IR SANT PAU), Sant Quint\u00ed 77-79, 08041 Barcelona, Spain"},{"name":"Grup de Neurofarmacologia Molecular, Institut de Neuroci\u00e8ncies, Universitat Aut\u00f2noma de Barcelona, 08193 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sylmara Esther","family":"Negrini-Ferrari","sequence":"additional","affiliation":[{"name":"Grup de Neurofarmacologia Molecular, Institut de Recerca Sant Pau (IR SANT PAU), Sant Quint\u00ed 77-79, 08041 Barcelona, Spain"},{"name":"Grup de Neurofarmacologia Molecular, Institut de Neuroci\u00e8ncies, Universitat Aut\u00f2noma de Barcelona, 08193 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4621-8457","authenticated-orcid":false,"given":"Olga","family":"Pol","sequence":"additional","affiliation":[{"name":"Grup de Neurofarmacologia Molecular, Institut de Recerca Sant Pau (IR SANT PAU), Sant Quint\u00ed 77-79, 08041 Barcelona, Spain"},{"name":"Grup de Neurofarmacologia Molecular, Institut de Neuroci\u00e8ncies, Universitat Aut\u00f2noma de Barcelona, 08193 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1152\/physrev.00045.2019","article-title":"Neuropathic Pain: From Mechanisms to Treatment","volume":"101","author":"Finnerup","year":"2021","journal-title":"Physiol. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2561","DOI":"10.1007\/s12035-024-04424-w","article-title":"The Voltage-Gated Calcium Channel \u03b12\u03b4 Subunit in Neuropathic Pain","volume":"62","author":"Guo","year":"2025","journal-title":"Mol. Neurobiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"265","DOI":"10.3233\/NRE-208002","article-title":"Peripheral neuropathic pain","volume":"47","author":"Murphy","year":"2020","journal-title":"NeuroRehabilitation"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"6782574","DOI":"10.1155\/prm\/6782574","article-title":"Emerging Therapeutic Modalities and Pharmacotherapies in Neuropathic Pain Management: A Systematic Review and Meta-Analysis of Parallel Randomized Controlled Trials","volume":"2024","author":"Kontor","year":"2024","journal-title":"Pain Res. Manag."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1016\/S1474-4422(25)00068-7","article-title":"Pharmacotherapy and Non-invasive Neuromodulation for Neuropathic Pain: A Systematic Review and Meta-Analysis","volume":"24","author":"Soliman","year":"2025","journal-title":"Lancet Neurol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Jiang, F., Xia, M., Zhang, Y., Chang, J., Cao, J., Zhang, Z., Qian, Z., and Yang, L. (2022). Cannabinoid receptor-2 attenuates neuroinflammation by promoting autophagy-mediated degradation of the NLRP3 inflammasome post spinal cord injury. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.993168"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Su\u00e1rez-Rojas, I., P\u00e9rez-Fern\u00e1ndez, M., Bai, X., Mart\u00ednez-Martel, I., Intagliata, S., Pittal\u00e0, V., Salerno, L., and Pol, O. (2023). The Inhibition of Neuropathic Pain Incited by Nerve Injury and Accompanying Mood Disorders by New Heme Oxygenase-1 Inducers: Mechanisms Implicated. Antioxidants, 12.","DOI":"10.3390\/antiox12101859"},{"key":"ref_8","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_9","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/j.pain.2004.12.022","article-title":"ERK is sequentially activated in neurons, microglia, and astrocytes by spinal nerve ligation and contributes to mechanical allodynia in this neuropathic pain model","volume":"114","author":"Zhuang","year":"2005","journal-title":"Pain"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.expneurol.2014.02.019","article-title":"Activation of spinal phosphatidylinositol 3-kinase\/protein kinase B mediates pain behavior induced by plantar incision in mice","volume":"255","author":"Xu","year":"2014","journal-title":"Exp. Neurol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1016\/j.expneurol.2007.05.029","article-title":"Activation of phosphatidylinositol 3-kinase and protein kinase B\/Akt in dorsal root ganglia and spinal cord contributes to the neuropathic pain induced by spinal nerve ligation in rats","volume":"206","author":"Xu","year":"2007","journal-title":"Exp. Neurol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1934","DOI":"10.1097\/j.pain.0000000000003536","article-title":"PI3K-mediated Kif1a DNA methylation contributes to neuropathic pain: An in vivo study","volume":"166","author":"Jiang","year":"2025","journal-title":"Pain"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1080\/13543784.2025.2473692","article-title":"Neuropathic pain management: A focused review of current treatments and novel data from main ongoing clinical trials","volume":"34","author":"Andrejic","year":"2025","journal-title":"Expert Opin. Investig. Drugs"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"108546","DOI":"10.1016\/j.pharmthera.2023.108546","article-title":"Neuropathic pain: From actual pharmacological treatments to new therapeutic horizons","volume":"251","author":"Thouaye","year":"2023","journal-title":"Pharmacol. Ther."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"10529","DOI":"10.1073\/pnas.1834309100","article-title":"Activation of CB2 cannabinoid receptors by AM1241 inhibits experimental neuropathic pain: Pain inhibition by receptors not present in the CNS","volume":"100","author":"Ibrahim","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"110257","DOI":"10.1016\/j.neuropharm.2024.110257","article-title":"The cannabinoid CB2 agonist LY2828360 suppresses neuropathic pain behavior and attenuates morphine tolerance and conditioned place preference in rats","volume":"265","author":"Guenther","year":"2025","journal-title":"Neuropharmacology"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Xu, K., Wu, Y., Tian, Z., Xu, Y., Wu, C., and Wang, Z. (2023). Microglial Cannabinoid CB2 Receptors in Pain Modulation. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24032348"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"229","DOI":"10.4103\/bc.bc_111_23","article-title":"Investigation of neuroprotective effects of H2 by CiteSpace-based bibliometric analysis","volume":"10","author":"Feng","year":"2024","journal-title":"Brain Circ."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Kawaguchi, M., Satoh, Y., Otsubo, Y., and Kazama, T. (2014). Molecular hydrogen attenuates neuropathic pain in mice. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0100352"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1007\/s12264-020-00597-1","article-title":"Neuroprotective Effects of Molecular Hydrogen: A Critical Review","volume":"37","author":"Chen","year":"2020","journal-title":"Neurosci. Bull."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Coral-P\u00e9rez, S., Mart\u00ednez-Martel, I., Mart\u00ednez-Serrat, M., Batall\u00e9, G., Bai, X., Leite-Panissi, C.R.A., and Pol, O. (2022). Treatment with Hydrogen-Rich Water Improves the Nociceptive and Anxio-Depressive-like Behaviors Associated with Chronic Inflammatory Pain in Mice. Antioxidants, 11.","DOI":"10.3390\/antiox11112153"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e70194","DOI":"10.1002\/mco2.70194","article-title":"Molecular Hydrogen Therapy: Mechanisms, Delivery Methods, Preventive, and Therapeutic Application","volume":"6","author":"Jin","year":"2025","journal-title":"MedComm"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"722","DOI":"10.1097\/ALN.0b013e318167af74","article-title":"Spinal Microglial and Perivascular Cell Cannabinoid Receptor Type 2 Activation Reduces Behavioral Hypersensitivity without Tolerance after Peripheral Nerve Injury","volume":"108","author":"DeLeo","year":"2008","journal-title":"Anesthesiology"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e677","DOI":"10.1097\/PR9.0000000000000677","article-title":"Heme oxygenase-1 inducer and carbon monoxide-releasing molecule enhance the effects of gabapentinoids by modulating glial activation during neuropathic pain in mice","volume":"3","author":"Godai","year":"2018","journal-title":"Pain Rep."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Bai, X., Batall\u00e9, G., Mart\u00ednez-Martel, I., and Pol, O. (2023). Hydrogen Sulfide Interacting with Cannabinoid 2 Receptors during Sciatic Nerve Injury-Induced Neuropathic Pain. Antioxidants, 12.","DOI":"10.3390\/antiox12061179"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.neuropharm.2016.12.008","article-title":"Synergistic attenuation of chronic pain using mu opioid and cannabinoid receptor 2 agonists","volume":"116","author":"Grenald","year":"2017","journal-title":"Neuropharmacology"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1467","DOI":"10.2147\/JPR.S138099","article-title":"Combination treatment of neuropathic pain: Danish expert recommendations based on a Delphi process","volume":"10","author":"Holbech","year":"2017","journal-title":"J. Pain Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"946","DOI":"10.2174\/1381612825666190506123038","article-title":"Therapeutic Efficacy of Molecular Hydrogen: A New Mechanistic Insight","volume":"25","author":"Ishibashi","year":"2019","journal-title":"Curr. Pharm. Des."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Mart\u00ednez-Serrat, M., Mart\u00ednez-Martel, I., Coral-P\u00e9rez, S., Bai, X., Batall\u00e9, G., and Pol, O. (2022). Hydrogen-Rich Water as a Novel Therapeutic Strategy for the Affective Disorders Linked with Chronic Neuropathic Pain in Mice. Antioxidants, 11.","DOI":"10.3390\/antiox11091826"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Agnes, J.P., Dos Santos, B., das Neves, R.N., Luciano, V.M.M., Benvenutti, L., Goldoni, F.C., Schran, R.G., Santin, J.R., Quint\u00e3o, N.L.M., and Zanotto-Filho, A. (2023). \u03b2-Caryophyllene Inhibits Oxaliplatin-Induced Peripheral Neuropathy in Mice: Role of Cannabinoid Type 2 Receptors, Oxidative Stress and Neuroinflammation. Antioxidants, 12.","DOI":"10.3390\/antiox12101893"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Ghiselli, F., Majer, R., Piva, A., and Grilli, E. (2024). Activation of cannabinoid receptor 2 by turmeric oleoresin reduces inflammation and oxidative stress in an osteoarthritis in vitro model. Front. Pharmacol., 15.","DOI":"10.3389\/fphar.2024.1488254"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Hashiesh, H.M., Sharma, C., Goyal, S.N., Jha, N.K., and Ojha, S. (2021). Pharmacological Properties, Therapeutic Potential and Molecular Mechanisms of JWH133, a CB2 Receptor-Selective Agonist. Front. Pharmacol., 12.","DOI":"10.3389\/fphar.2021.702675"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"784","DOI":"10.1089\/ars.2020.8257","article-title":"Loop Between NLRP3 Inflammasome and Reactive Oxygen Species","volume":"36","author":"Dominic","year":"2022","journal-title":"Antioxid. Redox Signal."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"5090","DOI":"10.1111\/bph.70116","article-title":"Cannabinoid CB2 receptor-mediated analgesia: Mechanism-based insights and therapeutic potential","volume":"182","author":"Guenther","year":"2025","journal-title":"Br. J. Pharmacol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e00464","DOI":"10.1016\/j.neurot.2024.e00464","article-title":"Neuroplasticity in the transition from acute to chronic pain","volume":"21","author":"Song","year":"2024","journal-title":"Neurotherapeutics"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Mart\u00ednez-Martel, I., Bai, X., Batall\u00e9, G., and Pol, O. (2022). New Treatment for the Cognitive and Emotional Deficits Linked with Paclitaxel-Induced Peripheral Neuropathy in Mice. Antioxidants, 11.","DOI":"10.3390\/antiox11122387"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"836","DOI":"10.1016\/j.jpain.2012.05.013","article-title":"Spinal cannabinoid receptor type 2 agonist reduces mechanical allodynia and induces mitogen-activated protein kinase phosphatases in a rat model of neuropathic pain","volume":"13","author":"Landry","year":"2012","journal-title":"J. Pain"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1694","DOI":"10.1248\/bpb.b14-00386","article-title":"Inhibition of mitogen-activated protein kinases phosphorylation plays an important role in the anti-nociceptive effect of pregabalin in zymosan-induced inflammatory pain model","volume":"37","author":"Jeong","year":"2014","journal-title":"Biol. Pharm. Bull."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1016\/j.neuint.2018.08.007","article-title":"Pregabalin and lacosamide ameliorate paclitaxel-induced peripheral neuropathy via inhibition of JAK\/STAT signaling pathway and Notch-1 receptor","volume":"120","author":"Ahmed","year":"2018","journal-title":"Neurochem. Int."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/j.neuropharm.2018.11.027","article-title":"Mechanical allodynia and enhanced responses to capsaicin are mediated by PI3K in a paclitaxel model of peripheral neuropathy","volume":"146","author":"Adamek","year":"2019","journal-title":"Neuropharmacology"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2253","DOI":"10.1038\/s41401-021-00853-8","article-title":"CB2 receptor activation in-hibits the phagocytic function of microglia through activating ERK\/AKT-Nurr1 signal pathways","volume":"43","author":"Han","year":"2022","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_42","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"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/24\/12155\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,18]],"date-time":"2025-12-18T09:19:42Z","timestamp":1766049582000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/24\/12155"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,18]]},"references-count":42,"journal-issue":{"issue":"24","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["ijms262412155"],"URL":"https:\/\/doi.org\/10.3390\/ijms262412155","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,18]]}}}