9967f0f1fe254c0af8a91b5932f01717 ijms-27-03051.pdf aad732b44c4ae83f263e4f7465460759c2a64a60 ijms-27-03051.pdf ba8cd6a48e575674b4f6058bab3f6ac3d7675c50a2212b36a99755176d77608a ijms-27-03051.pdf Title: Molecular Hydrogen Reverses Nociplastic Pain and Depressive-like Behaviors via Region- and Sex-Dependent Central Mechanisms Subject: Fibromyalgia is a chronic nociplastic pain condition frequently accompanied by affective disturbances, particularly depression, for which effective treatments remain limited. Increasing evidence implicates central oxidative stress, maladaptive synaptic plasticity, and neuroinflammatory alterations in its pathophysiology. This study investigated the therapeutic effects of molecular hydrogen (H2) in a reserpine-induced murine model of fibromyalgia, with emphasis on sex-dependent and region-specific mechanisms. Male and female C57BL/6 mice received repeated reserpine injections to induce fibromyalgia-like symptoms. Mechanical allodynia, thermal hyperalgesia, cold allodynia, and depressive-like behaviors were assessed, followed by molecular analyses in the spinal cord and amygdala. Reserpine induced persistent nociceptive hypersensitivity and depressive-like behaviors in both sexes, with earlier cold allodynia in females. Hydrogen-rich water (HRW) progressively reversed mechanical and thermal hypersensitivity and rapidly abolished cold allodynia, showing greater efficacy in females. HRW also normalized depressive-like behaviors in both sexes. At the molecular level, HRW reduced spinal oxidative stress and ERK-dependent plasticity without altering spinal NLRP3 expression, whereas it fully reversed NLRP3 upregulation and HO-1 downregulation in the amygdala. HRW additionally engaged sex-dependent antioxidant pathways in the spinal cord. These findings indicate that H2 alleviates sensory and affective alterations through region- and sex-dependent central mechanisms, supporting HRW as a promising therapeutic strategy for nociplastic pain and its affective comorbidities. Keywords: depression; fibromyalgia; hydrogen-rich water; inflammation; molecular hydrogen; nociplastic pain; oxidative stress Author: Sylmara Esther Negrini-Ferrari, Ignacio Martínez-Martel and Olga Pol Creator: LaTeX with hyperref Producer: pdfTeX-1.40.25; modified using OpenPDF 1.4.2 CreationDate: Fri Mar 27 09:23:50 2026 CET ModDate: Fri Mar 27 09:28:47 2026 CET Custom Metadata: yes Metadata Stream: no Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 17 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 1677563 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- VNQZRP+URWPalladioL-Ital Type 1 Custom yes yes yes 134 0 HPBFBG+URWPalladioL-Bold Type 1 Custom yes yes yes 135 0 QBLPJB+VnURWPalladioL Type 1 Custom yes yes yes 136 0 KRDNTX+URWPalladioL-Roma Type 1 Custom yes yes yes 137 0 VYVZGZ+CMSY10 Type 1 Builtin yes yes yes 231 0 FPAOEK+PalatinoLinotype-Italic CID TrueType Identity-H yes yes yes 213 0 FPAODI+PalatinoLinotype-Bold CID TrueType Identity-H yes yes yes 214 0 FPAODJ+PalatinoLinotype-Roman CID TrueType Identity-H yes yes yes 215 0 FPAOEK+PalatinoLinotype-Italic CID TrueType Identity-H yes yes yes 280 0 FPAODI+PalatinoLinotype-Bold CID TrueType Identity-H yes yes yes 281 0 FPAODJ+PalatinoLinotype-Roman CID TrueType Identity-H yes yes yes 282 0 FPAOEK+PalatinoLinotype-Italic CID TrueType Identity-H yes yes yes 302 0 FPAODI+PalatinoLinotype-Bold CID TrueType Identity-H yes yes yes 303 0 FPAODJ+PalatinoLinotype-Roman CID TrueType Identity-H yes yes yes 304 0 FPAOEK+PalatinoLinotype-Italic CID TrueType Identity-H yes yes yes 348 0 FPAODI+PalatinoLinotype-Bold CID TrueType Identity-H yes yes yes 349 0 FPAODJ+PalatinoLinotype-Roman CID TrueType Identity-H yes yes yes 350 0 FPAOEK+PalatinoLinotype-Italic CID TrueType Identity-H yes yes yes 401 0 FPAODI+PalatinoLinotype-Bold CID TrueType Identity-H yes yes yes 402 0 FPAODJ+PalatinoLinotype-Roman CID TrueType Identity-H yes yes yes 403 0 FPAOEK+PalatinoLinotype-Italic CID TrueType Identity-H yes yes yes 431 0 FPAODI+PalatinoLinotype-Bold CID TrueType Identity-H yes yes yes 432 0 FPAODJ+PalatinoLinotype-Roman CID TrueType Identity-H yes yes yes 433 0 FPAOEK+PalatinoLinotype-Italic CID TrueType Identity-H yes yes yes 492 0 FPAODI+PalatinoLinotype-Bold CID TrueType Identity-H yes yes yes 493 0 FPAODJ+PalatinoLinotype-Roman CID TrueType Identity-H yes yes yes 494 0 VVSYYB+EURM10 Type 1 Builtin yes yes yes 641 0 Jhove (Rel. 1.28.0, 2023-05-18) Date: 2026-04-16 03:09:03 CEST RepresentationInformation: ijms-27-03051.pdf ReportingModule: PDF-hul, Rel. 1.12.4 (2023-03-16) LastModified: 2026-04-15 06:18:35 CEST Size: 1677563 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 763 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: Reserpine Induces Persistent Mechanical Allodynia, Thermal Hyperalgesia and Cold Allodynia in Male and Female Mice Item: Title: HRW Reverses Reserpine-Induced Nociceptive Hypersensitivity Item: Title: Treatment with HRW Inhibited the Depressive-like Behaviors Associated with Fibromyalgia Item: Title: The Effect of HRW Treatment on the Expression of 4-HNE, NLRP3 and p-ERK 1/2 in the Spinal Cord of Male and Female Reserpine-Injected Mice Item: Title: The Effect of HRW Treatment on the Expression of HO-1, NQO1 and SOD-1 in the Spinal Cord of Male and Female Reserpine-Injected Mice Item: Title: The Effect of HRW Treatment on the Expression of 4-HNE, NLRP3 and p-ERK 1/2 in the Amygdala of Male and Female Reserpine-Injected Mice Item: Title: The Effect of HRW Treatment on the Expression of HO-1, NQO1 and SOD-1 in the Amygdala of Male and Female Reserpine-Injected Mice Item: Title: Discussion Item: Title: Materials and Methods Children: Item: Title: Animals Item: Title: Fibromyalgia Induction Item: Title: Nociceptive Tests Item: Title: Depressive-like Behaviors Item: Title: Drugs Item: Title: Experimental Protocol Item: Title: Western Blotting Item: Title: Statistical Analysis Item: Title: Conclusions Item: Title: References Info: Title: Molecular Hydrogen Reverses Nociplastic Pain and Depressive-like Behaviors via Region- and Sex-Dependent Central Mechanisms Author: Sylmara Esther Negrini-Ferrari, Ignacio Martínez-Martel and Olga Pol Subject: Fibromyalgia is a chronic nociplastic pain condition frequently accompanied by affective disturbances, particularly depression, for which effective treatments remain limited. Increasing evidence implicates central oxidative stress, maladaptive synaptic plasticity, and neuroinflammatory alterations in its pathophysiology. This study investigated the therapeutic effects of molecular hydrogen (H2) in a reserpine-induced murine model of fibromyalgia, with emphasis on sex-dependent and region-specific mechanisms. Male and female C57BL/6 mice received repeated reserpine injections to induce fibromyalgia-like symptoms. Mechanical allodynia, thermal hyperalgesia, cold allodynia, and depressive-like behaviors were assessed, followed by molecular analyses in the spinal cord and amygdala. Reserpine induced persistent nociceptive hypersensitivity and depressive-like behaviors in both sexes, with earlier cold allodynia in females. Hydrogen-rich water (HRW) progressively reversed mechanical and thermal hypersensitivity and rapidly abolished cold allodynia, showing greater efficacy in females. HRW also normalized depressive-like behaviors in both sexes. At the molecular level, HRW reduced spinal oxidative stress and ERK-dependent plasticity without altering spinal NLRP3 expression, whereas it fully reversed NLRP3 upregulation and HO-1 downregulation in the amygdala. HRW additionally engaged sex-dependent antioxidant pathways in the spinal cord. These findings indicate that H2 alleviates sensory and affective alterations through region- and sex-dependent central mechanisms, supporting HRW as a promising therapeutic strategy for nociplastic pain and its affective comorbidities. 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