Neuropathic pain manifested with allodynia and hyperalgesia usually becomes a chronic condition accompanied with mood disorders. Clinical therapies for neuropathic pain are still unsatisfactory with notable side effects. Recent studies have reported the protective role of molecular hydrogen (H2) in different diseases including neurological disorders, such as Alzheimer’s as well as its antidepressant activities in animals with chronic stress. This study explored the effects of treatment with hydrogen-rich water (HRW) in male mice with neuropathic pain induced by the chronic constriction of the sciatic nerve (CCI) and the accompanying affective deficits. The likely pathways implied in the HRW analgesic activity, as well as the interaction between heme oxygenase 1 (HO-1) enzyme and H2 during neuropathic pain were also studied. The results showed: (i) the inhibitory effects of the repetitive treatment with HRW on the allodynia and hyperalgesia provoked by CCI; (ii) the anxiolytic and antidepressant actions of HRW in animals with neuropathic pain; (iii) the contribution of the antioxidant enzymes (HO-1 and NAD(P)H: quinone oxidoreductase 1) and the ATP sensitive potassium channels in the painkiller activities of HRW during neuropathic pain; (iv) a positive interaction between the HO-1 and H2 systems in inhibiting the CCI-induced neuropathy; and (v) the antioxidant, antinociceptive, anti-inflammatory and/or antiapoptotic features of HRW treatment in the dorsal root ganglia and/or amygdala of sciatic nerve-injured mice. This study demonstrates new protective actions of H2 and suggests that treatment with HRW might be an interesting therapeutic strategy for chronic neuropathic pain and its associated mood disorders.

Chronic inflammatory pain is manifested in many diseases. The potential use of molecular hydrogen (H2) as a new therapy for neurological disorders has been demonstrated. Recent studies prove its analgesic properties in animals with neuropathic pain, but the possible antinociceptive, antidepressant, and/or anxiolytic actions of H2 during persistent inflammatory pain have not been investigated. Therefore, using male mice with chronic inflammatory pain incited by the subplantar injection of complete Freud’s adjuvant (CFA), we assessed the actions of hydrogen-rich water (HRW) systemically administered on: (1) the nociceptive responses and affective disorders associated and (2) the oxidative (4-hydroxy-2-nonenal; 4-HNE), inflammatory (phosphorylated-NF-kB inhibitor alpha; p-IKBα), and apoptotic (Bcl-2-like protein 4; BAX) changes provoked by CFA in the paws and amygdala. The role of the antioxidant system in the analgesia induced by HRW systemically and locally administered was also determined. Our results revealed that the intraperitoneal administration of HRW, besides reducing inflammatory pain, also inhibited the depressive- and anxiolytic-like behaviors associated and the over expression of 4-HNE, p-IKBα, and BAX in paws and amygdala. The contribution of the nuclear factor erythroid 2-related factor 2/heme oxygenase 1 and NAD(P)H: quinone oxidoreductase 1 pathway in the analgesic activities of HRW, systemically or locally administered, was also shown. These data revealed the analgesic, antidepressant, and anxiolytic actions of HRW. The protective, anti-inflammatory, and antioxidant qualities of this treatment during inflammatory pain were also demonstrated. Therefore, this study proposes the usage of HRW as a potential therapy for chronic inflammatory pain and linked comorbidities.