Sex-specific electrophysiological and behavioral responses to nitrous oxide in a murine model of neuropathic pain.

内容摘要

Chronic pain-depression comorbidity is characterized by sensory hypersensitivity and emotional dysregulation, and has been linked to alterations in prefrontal network connectivity. It represents a major therapeutic challenge due to its pronounced sex differences in symptom manifestation and increased treatment resistance. Nitrous oxide (N₂O), an inhalational anesthetic traditionally used for its analgesic properties, has recently emerged as a potential rapid-acting antidepressant, with evidence suggesting both rapid and sustained antidepressant effects. Here, we evaluated the behavioral and electrophysiological effects of N₂O (50%, 1 h) in adult male and female mice subjected to the chronic constriction injury (CCI) model of neuropathic pain, assessing its potential to simultaneously target nociceptive and affective symptoms, as well as locomotor behavior. N₂O reduced locomotor activity in both sexes, with longer-lasting effects in males. EEG recordings revealed decreased low-frequency spectral power in both sham and CCI animals, with more widespread effects in females. In the acetone test, N₂O produced analgesia in CCI males but no significant effect in females, while stimulus application increased oscillatory EEG activity across groups and sexes. Notably, CCI females showed an attenuated electrophysiological response compared with Sham-Air controls. In sham animals, N₂O reduced post-stimulus power, whereas in CCI mice it restored prefrontal EEG activity, enhancing the electrophysiological responses in both sexes. In the tail suspension test, only CCI males exhibited a prodepressive phenotype, while no antidepressant-like effects were observed in either sex 24 h post-treatment. These findings demonstrate sex-specific behavioral and neurophysiological responses to N₂O, highlighting the importance of incorporating sex as a biological variable in NMDA receptor-targeted interventions. Chronic pain and depression often occur together and can severely affect quality of life. People living with both conditions frequently experience increased pain sensitivity, low mood, reduced motivation, and poor response to treatment. Importantly, men and women can experience these symptoms differently, yet many studies do not adequately investigate these sex differences. Nitrous oxide (N₂O), commonly known as “laughing gas,” is used in clinical practice for pain relief and has recently attracted interest as a potential fast-acting antidepressant. However, its effects in chronic pain–related depression, as well as potential differences between males and females, have not been explored. In this study, we investigated how N₂O affects pain- and mood-related behaviors and brain activity in male and female mice with nerve injury–induced chronic pain. After N₂O exposure, we evaluated movement activity, pain sensitivity, depressive-like behavior, and electroencephalographic (EEG) activity. Our findings reveal that N₂O produced distinct behavioral and EEG responses in male and female mice. Particularly, N₂O similarly reduced movement activity and altered EEG activity in both sexes, although the timing and magnitude of these effects differed between sexes. N₂O reduced pain sensitivity in male mice with chronic pain, but not in females, and did not produce clear antidepressant-like effects 24 h after treatment in either sex. Overall, our findings show that males and females respond differently to N₂O treatment and highlight the importance of considering sex differences when developing new treatments for chronic pain and depression.