Hydrogen-Rich Water Potentiates Cannabinoid- and Gabapentinoid-Induced Analgesia in Neuropathic Pain

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.