# Hydrogen-Rich Water Potentiates Cannabinoid- and Gabapentinoid-Induced Analgesia in Neuropathic Pain.
> 水素水はカンナビノイドおよびガバペンチノイドによる神経障害性疼痛の鎮痛効果を増強する


## Abstract

Using male C57BL/6 mice subjected to chronic constriction injury of the sciatic nerve as a neuropathic pain model, this study investigated whether hydrogen-rich water (HRW) could enhance the analgesic actions of JWH-133 (a selective CB2 receptor agonist) and pregabalin (a gabapentinoid). Mechanical allodynia, thermal hyperalgesia, and cold allodynia were quantified after single-agent and combination administrations. Each compound alone reduced pain-related behaviors in a dose-dependent fashion, but co-administration with HRW produced substantially greater pain relief. Western blot analyses of dorsal root ganglia revealed that combined regimens significantly lowered levels of the oxidative stress marker 4-HNE, the inflammasome component NLRP3, the synaptic plasticity indicator p-ERK, and the nociceptive signaling mediator p-AKT. These results indicate that HRW may serve as an effective adjuvant to cannabinoid and gabapentinoid agents, potentially allowing lower drug doses while maintaining or improving analgesic efficacy.

### Mechanism

HRW's antioxidant and anti-inflammatory properties appear to suppress NLRP3 inflammasome activation, p-ERK-mediated maladaptive synaptic plasticity, and p-AKT nociceptive signaling in dorsal root ganglia, thereby reducing central sensitization following peripheral nerve injury and potentiating drug-induced analgesia.

## Bibliographic

- **Authors**: Tort NA, Negrini-Ferrari SE, Pol O
- **Journal**: Int J Mol Sci
- **Year**: 2025 (2025-12-18)
- **PMID**: [41465581](https://pubmed.ncbi.nlm.nih.gov/41465581/)
- **DOI**: [10.3390/ijms262412155](https://doi.org/10.3390/ijms262412155)
- **PMC**: [PMC12734278](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12734278/)
- **Study type**: animal study
- **Delivery route**: hydrogen-rich water
- **Effect reported**: positive

## Delivery context

Hydrogen-rich water is a low-risk delivery route, but the achievable systemic hydrogen dose is bounded. For clinical applications, inhalation is the most efficient route; inhalation, however, carries explosion risk, and concentration matters (empirical LFL of 10% applies to inhalation environments; high-concentration devices are documented in the Consumer Affairs Agency accident database and are not recommended).

## Safety notes

Hydrogen-rich water is a low-risk delivery route, but the achievable systemic hydrogen dose is bounded. For clinical applications, inhalation is the most efficient route; inhalation, however, carries explosion risk, and concentration matters (empirical LFL of 10% applies to inhalation environments; high-concentration devices are documented in the Consumer Affairs Agency accident database and are not recommended).

See also:
- [Inhalation concentration and LFL / UFL](https://h2-papers.org/en/safety-notes/inhalation-concentration)
- [Consumer Affairs Agency accident cases](https://h2-papers.org/en/safety-notes/accident-cases)
- [Inhalation safety threshold lineage](https://h2-papers.org/en/safety-notes/lineage)

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> **Cite as**: H2 Papers — PMID 41465581. https://h2-papers.org/en/papers/41465581
> **Source**: PubMed PMID [41465581](https://pubmed.ncbi.nlm.nih.gov/41465581/)