b24e4afe9c0a35ab9810cee7e56c7ae7 ijms-26-12155-v2.pdf d715110ebb7f3190cf1a0b1440609b101e274500 ijms-26-12155-v2.pdf 82f9332fa75d9bccc70546d563122602a8be511157758eb31feabe16bea4caae ijms-26-12155-v2.pdf Title: Hydrogen-Rich Water Potentiates Cannabinoid- and Gabapentinoid-Induced Analgesia in Neuropathic Pain Subject: 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. Keywords: neuropathic pain; molecular hydrogen; cannabinoids; gabapentinoids; analgesia Author: Nuria Andrea Tort, Sylmara Esther Negrini-Ferrari and Olga Pol Creator: LaTeX with hyperref Producer: pdfTeX-1.40.25; modified using OpenPDF 1.4.2 CreationDate: Mon Dec 22 10:07:54 2025 CET ModDate: Mon Dec 22 10:11:13 2025 CET Custom Metadata: yes Metadata Stream: no Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 18 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 2113512 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- AGUZUB+URWPalladioL-Ital Type 1 Custom yes yes yes 133 0 LRHRCY+VnURWPalladioL Type 1 Custom yes yes yes 134 0 EWFDSQ+URWPalladioL-Bold Type 1 Custom yes yes yes 135 0 MXHUUA+URWPalladioL-Roma Type 1 Custom yes yes yes 136 0 ACZNUE+EURM10 Type 1 Builtin yes yes yes 182 0 QMDDXF+CMSY10 Type 1 Builtin yes yes yes 237 0 FPMPBN+PalatinoLinotype TrueType WinAnsi yes yes no 220 0 FPMPBM+PalatinoLinotype CID TrueType Identity-H yes yes yes 221 0 FPMPBL+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 274 0 FPMPBN+PalatinoLinotype TrueType WinAnsi yes yes no 275 0 FPMPBL+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 296 0 FPMPBN+PalatinoLinotype TrueType WinAnsi yes yes no 297 0 FPMPBP+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 298 0 FPMPJN+PalatinoLinotype TrueType MacRoman yes yes no 388 0 FPMPBN+PalatinoLinotype TrueType WinAnsi yes yes no 389 0 FPMPBP+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 390 0 FPMPBL+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 409 0 FPMPBN+PalatinoLinotype TrueType WinAnsi yes yes no 410 0 UJUUJI+PazoMath Type 1 Builtin yes yes yes 524 0 FPMPJN+PalatinoLinotype TrueType MacRoman yes yes no 468 0 FPMPBN+PalatinoLinotype TrueType WinAnsi yes yes no 469 0 Jhove (Rel. 1.28.0, 2023-05-18) Date: 2026-01-18 03:10:35 CET RepresentationInformation: ijms-26-12155-v2.pdf ReportingModule: PDF-hul, Rel. 1.12.4 (2023-03-16) LastModified: 2026-01-17 15:39:23 CET Size: 2113512 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 717 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: ViewerPreferences: HideToolbar: false HideMenubar: false HideWindowUI: false FitWindow: true CenterWindow: false DisplayDocTitle: false NonFullScreenPageMode: UseNone Direction: L2R ViewArea: CropBox ViewClip: CropBox PrintArea: CropBox PageClip: CropBox PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Item: Title: Results Children: Item: Title: Validation of the CCI Mouse Model Item: Title: Dose-Dependent Antinociceptive Effects of HRW in Animals with NP Item: Title: Dose-Dependent Antinociceptive Effects of JWH-133 in Animals with NP Item: Title: Dose-Dependent Antinociceptive Effects of Pregabalin in Animals with NP Item: Title: The Antinociceptive Effects of the Co-Treatment of HRW and JWH-133 in Animals with NP Item: Title: The Antinociceptive Effects of the Co-Treatment of HRW and Pregabalin in Animals with NP Item: Title: Expression of 4-HNE, NLRP3, p-ERK 1/2, and p-AKT in the DRG of CCI Mice Item: Title: Discussion Item: Title: Materials and Methods Children: Item: Title: Animal Experimental Models Item: Title: Neuropathic Pain Model Item: Title: Nociceptive Tests Item: Title: Pharmacological Treatments Item: Title: Experimental Design Item: Title: Western Blotting Item: Title: Statistical Analysis Item: Title: Conclusions Item: Title: References Info: Title: Hydrogen-Rich Water Potentiates Cannabinoid- and Gabapentinoid-Induced Analgesia in Neuropathic Pain Author: Nuria Andrea Tort, Sylmara Esther Negrini-Ferrari and Olga Pol Subject: 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. 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