Nitrous oxide (N₂O) at 50% concentration for one hour produced sex-specific effects on behavior and brain activity in mice with chronic pain. In males with neuropathic pain, N₂O reduced pain sensitivity, while females showed no pain relief. The drug decreased movement in both sexes, with longer-lasting effects in males. Brain recordings showed N₂O reduced low-frequency electrical activity in all mice, with stronger effects in females. In animals without pain, N₂O dampened brain responses to stimulation, but in pain-model mice it restored prefrontal activity. No antidepressant-like effects appeared 24 hours after treatment in either sex. These results indicate that N₂O's effects depend on sex and pain state, emphasizing the need to consider sex in NMDA receptor-based treatments.
A brief exposure to nitrous oxide (N2O) causes a drop in body temperature, reduced movement, enhanced slow-wave brain activity, decreased brain glucose use, and increased phosphorylation of TrkB, GSK3β, and p70S6K in the medial prefrontal cortex of adult male mice. Preventing the hypothermic response in a chronic stress model of depression weakened the antidepressant-like behavioral effects of N2O in the saccharin preference test. These findings indicate that N2O treatment modulates TrkB signaling and related neurotrophic pathways in a temperature-dependent manner, linking altered thermoregulation and energy expenditure to antidepressant-like behavioral responses.