Nitrous Oxide Persistently Alleviates Pain Hypersensitivity in Neuropathic Rats: A Dose-Dependent Effect

Abstract

BACKGROUND: Despite numerous pharmacological approaches, there are no common analgesic drugs that produce meaningful relief for the majority of patients with neuropathic pain. Although nitrous oxide (N₂O) is a weak analgesic that acts via opioid-dependent mechanisms, it is also an antagonist of the N-methyl-D-aspartate receptor (NMDAR). The NMDAR plays a critical role in the development of pain sensitization induced by nerve injury.OBJECTIVE: Using the chronic constriction injury of the sciatic nerve in male rats as a preclinical model of neuropathic pain, the first aim of the present study was to evaluate the lowest N₂O concentration and the shortest time of N₂O postinjury exposure that would produce persistent relief of neuropathic pain. The second aim was to compare the effects of N₂O with gabapentin, a reference drug used in human neuropathic pain relief.METHODS: Changes in the nociceptive threshold were evaluated using the paw pressure vocalization test in rats.RESULTS: Among the various N₂O concentrations tested, which ranged from 25% to 50%, only 50% N₂O single exposure for 1 h 15 min induced a persistent (minimum of three weeks) and significant (60%) reduction in pain hypersensitivity. A single gabapentin dose (75 mg/kg to 300 mg/kg, intraperitoneally) induced an acute (1 h to 1 h 30 min) dose-dependent effect, but not a persistent effect such as that observed with N₂O.CONCLUSIONS: These preclinical results suggest that N₂O is advantageous for long-lasting neuropathic pain relief after sciatic nerve injury compared with other drugs used in humans such as gabapentinoids or NMDAR antagonists. The present preclinical study provides a rationale for developing comparative clinical studies.