Nitrous oxide persistently alleviates pain hypersensitivity in neuropathic rats: A dose-dependent effect

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 (N(2)O) 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 N(2)O concentration and the shortest time of N(2)O postinjury exposure that would produce persistent relief of neuropathic pain. The second aim was to compare the effects of N(2)O 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 N(2)O concentrations tested, which ranged from 25% to 50%, only 50% N(2)O 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 N(2)O. CONCLUSIONS: These preclinical results suggest that N(2)O 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.